Treatment of chemokine mediated diseases

ABSTRACT

Methods of treating chemokine-mediated diseases are disclosed. The methods comprise the administration of CXC-Chemokine receptor antagonists of the formula  
                 
 
     or pharmaceutically acceptable salts or solvates thereof, in combination with other classes of pharmaceutical compounds. The chemokine-mediated diseases include acute and chronic inflammatory disorders, psoriasis, cystic fibrosis, asthma and cancer. Also disclosed are novel compounds of formula (I).

REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/365,314 filed Mar. 18, 2002, the disclosure of whichis incorporated herein by reference thereto.

FIELD OF THE INVENTION

[0002] This invention relates to the treatment of chemokine mediateddiseases using CXC chemokine receptor antagonists in combination (orassociation) with other pharmaceutical compounds.

BACKGROUND OF THE INVENTION

[0003] Chemokines are chemotactic cytokines that are released by a widevariety of cells to attract macrophages, T-cells, eosinophils,basophils, neutrophils and endothelial cells to sites of inflammationand tumor growth. There are two main classes of chemokines, theCXC-chemokines and the CC— chemokines. The class depends on whether thefirst two cysteines are separated by a single amino acid(CXC-chemokines) or are adjacent (CC-chemokines). The CXC-chemokinesinclude interleukin-8 (IL-8), neutrophil-activating protein-1 (NAP-1),neutrophil-activating protein-2 (NAP-2), GROα, GROβ, GROγ, ENA-78,GCP-2, IP-10, MIG and PF4. CC chemokines include RANTES, MIP-1α, MIP-2β,monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin.Individual members of the chemokine families are known to be bound by atleast one chemokine receptor, with CXC-chemokines generally bound bymembers of the CXCR class of receptors, and CC-chemokines by members ofthe CCR class of receptors. For example, IL-8 is bound by the CXCR-1 andCXCR-2 receptors.

[0004] Since CXC-chemokines promote the accumulation and activation ofneutrophils, these chemokines have been implicated in a wide range ofacute and chronic inflammatory disorders including psoriasis andrheumatoid arthritis. Baggiolini et al., FEBS Left. 307, 97 (1992);Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al.,Annu. Fev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87,463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992);Donnely et al., Lancet 341,643(1993).

[0005] Hence, the CXC-chemokine receptors represent promising targetsfor the development of novel anti-inflammatory agents.

[0006] There remains a need for an improved method of treatingCXC-chemokine mediated diseases. For example, conditions associated withan increase in IL-8 production (which is responsible for chemotaxis ofneutrophil and T-cell subsets into the inflammatory site) would benefitby an improved method that inhibits IL-8 receptor binding. Such animproved method is provided by this invention.

SUMMARY OF THE INVENTION

[0007] This invention provides a method of treating a CXC chemokinemediated disease comprising administering to a patient (i.e., a mammal,e.g. human) in need of such treatment, a therapeutically effectiveamount of:

[0008] (a) One or more (e.g., one) compounds of the formula (I):

[0009] or a pharmaceutically acceptable salt or solvate thereof; and

[0010] (b) One or more drugs, agents or therapeutics useful for thetreatment of chemokine mediated diseases.

[0011] In one embodiment, the invention provides a method of treating achemokine mediated disease comprising administering to a patient (e.g.,a human) in need of such treatment, an effective amount of one or more(e.g., one) compounds of formula (I) in combination (or association)with an effective amount of one or more disease modifying antirheumaticdrugs (DMARDs) such as, for example, methotrexate, azathioptrine,luflunomide, penicillamine, gold salts, mycophenolate, mofetil,cyclophosphamide and the like.

[0012] In another embodiment, the invention provides a method oftreating a chemokine mediated disease comprising administering to apatient (e.g., a human) in need of such treatment, an effective amountof one or more (e.g., one) compounds of formula (I) in combination (orassociation) with an effective amount of one or more nonsteroidalanti-inflammatory drugs (NSAIDS) such as, for example, piroxicam,ketoprofen, naproxen, indomethacin, ibuprofen and the like.

[0013] In another embodiment the invention provides a method of treatinga chemokine mediated disease comprising administering to a patient(e.g., a human) in need of such treatment, an effective amount of one ormore (e.g., one) compounds of formula (I) in combination (orassociation) with an effective amount of one or more compounds selectedfrom the group consisting of:

[0014] (a) a disease modifying antirheumatic drug (such as, for example,methotrexate, azathioptrine, luflunomide, penicillamine, gold salts,mycophenolate, mofetil, cyclophosphamide and the like);

[0015] (b) a nonsteroidal anitinflammatory drug (such as, for example,piroxicam, ketoprofen, naproxen, indomethacin, ibuprofen and the like);

[0016] (c) COX-2 selective inhibitors such as, for example, rofecoxiband celecoxib;

[0017] (d) COX-1 inhibitors such as, for example, piroxicam;

[0018] (e) immunosuppressives such as, for example, methotrexate,cyclosporin, leflunimide, tacrolimus, rapamycin or sulfasalazine; and

[0019] (f) steroids such as, for example, betamethasone, cortisone,prednisone or dexamethasone.

[0020] In another embodiment the invention provides a method of treatinga chemokine mediated disease comprising administering to a patient(e.g., a human) in need of such treatment, an effective amount of one ormore (e.g., one) compounds of formula (I) in combination (orassociation) with an effective amount of one or more compounds selectedfrom the group consisting of:

[0021] (a) a disease modifying antirheumatic drug (such as, for example,methotrexate, azathioptrine, luflunomide, penicillamine, gold salts,mycophenolate, mofetil, cyclophosphamide and the like);

[0022] (b) a nonsteroidal anitinflammatory drug (such as, for example,piroxicam, ketoprofen, naproxen, indomethacin, ibuprofen and the like);

[0023] (c) COX-2 selective inhibitors such as, for example, rofecoxiband celecoxib;

[0024] (d) COX-1 inhibitors such as, for example, piroxicam;

[0025] (e) immunosuppressives such as, for example, methotrexate,cyclosporin, leflunimide, tacrolimus, rapamycin or sulfasalazine;

[0026] (f) steroids such as, for example, betamethasone, cortisone,prednisone or dexamethasone;

[0027] (g) a biological response modifier and

[0028] (h) other anti-inflammatory agents or therapeutics useful for thetreatment of chemokine mediated diseases.

[0029] In another embodiment, the invention provides a method oftreating a chemokine mediated disease comprising administering to apatient (e.g., a human) in need of such treatment, an effective amountof one or more (e.g., one) compounds of formula (I), in combination (orassociation) with an effective amount of one or more biological responsemodifiers (BRMs) such as, for example, anti-TNF antagonists includingantibodies and/or receptors/receptor fragments, IL-1 antagonists,anti-CD40, anti-CD28, IL-10, anti-adhesion molecules and the like.

[0030] In another embodiment, the invention provides a method oftreating a chemokine mediated disease comprising administering to apatient (e.g., a human) in need of such treatment, an effective amountof one or more (e.g., one) compounds of formula (I) in combination (orassociation) with an effective amount of one or more compounds selectedfrom the group consisting of:

[0031] a) anti-inflammatory agents such as, for example, p38 kinaseinhibitors, PDE4 inhibitors, and TACE inhibitors;

[0032] b) chemokine receptor antagonists such as, for example,thalidomide;

[0033] c) leukotriene inhibitors; and

[0034] d) other small molecule inhibitors of pro-inflammatory cytokineproduction.

[0035] In another embodiment, the invention provides a method oftreating a chemokine mediated disease, said disease being a pulmonarydisease (e.g., COPD, asthma, or cystic fibrosis) comprisingadministering to a patient (e.g., a human) in need of such treatment, aneffective amount of one or more (e.g., one) compounds of formula (I) incombination (or association) with an effective amount of one or morecompounds selected from the group consisting of: glucocorticoids,5-lipoxygenase inhibitors, β-2 adrenoceptor agonists, muscarinic M1antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists,bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors,MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors,histamine H1 antagonists, histamine H3 antagonists, dopamine agonists,adenosine A2 agonists, NK1 and NK2 antagonists, GABA-b agonists,nociceptin agonists, expectorants, mucolytic agents, decongestants,antioxidants, anti-IL-8 anti-bodies, anti-IL-5 antibodies, anti-IgEantibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors,and growth hormones. Agents that belong to these classes include, butare not limited to, beclomethasone, mometasone, ciclesonide, budesonide,fluticasone, albuterol, salmeterol, formoterol, loratadine,desloratadine, tiotropium bromide, MSI-ipratropium bromide, montelukast,theophilline, cilomilast, roflumilast, cromolyn, ZD-4407, talnetant,LTB-019, revatropate, pumafentrine, CP955, AR-C-89855, BAY-19-8004,GW-328267, QAB-149, DNK-333, YM-40461 and TH-9506 (or pharmaceuticallyacceptable formulations thereof).

[0036] In another embodiment, the invention provides a method oftreating a chemokine mediated disease, said disease being multiplesclerosis comprising administering to a patient in need of suchtreatment a therapeutically effective amount of one or more (e.g., one)compounds of formula (I) in combination (or association) with aneffective amount of one or more compounds selected from the groupconsisting of methotrexate, cyclosporin, leflunimide, sulfasalazine,β-methasone, β-interferon, glatiramer acetate, prednisone, etonercept,infliximab, and formulations thereof.

[0037] In another embodiment, the invention provides a method oftreating a chemokine mediated disease, said disease being rheumatoidarthritis comprising administering to a patient in need of suchtreatment an effective amount of one or more (e.g., one) compounds offormula (I) in combination (or association) with an effective amount ofone or more compounds selected from the group consisting of a COX-2inhibitor, a COX inhibitor, an immunosuppressive, a steroid, a PDE IVinhibitor, an anti-TNF-α compound, MMP inhibitors, glucocorticoids,chemokine inhibitors, CB2-selective inhibiitors, other classes ofcompounds indicated for the treatment of rheumatoid arthritis, andformulations thereof.

[0038] In another embodiment, the invention provides a method oftreating a chemokine mediated disease, said disease being rheumatoidarthritis comprising administering to a patient in need of suchtreatment an effective amount of one or more (e.g., one) compounds offormula (I) in combination (or association) with an effective amount ofone or more compounds selected from the group consisting of a COX-2inhibitor, a COX inhibitor, an immunosuppressive, a steroid, a PDE IVinhibitor, an anti-TNF-α compound, MMP inhibitors, glucocorticoids,chemokine inhibitors, and CB2-selective inhibitors.

[0039] In another embodiment, the invention provides a method oftreating a chemokine mediated disease, said disease being stroke andcardiac reperfusion injury comprising administering to a patient in needof such treatment an effective amount of one or more (e.g., one)compounds of formula (I) in combination (or association) with aneffective amount of one or more compounds selected from the groupconsisting of thrombolitics, antiplatelet agents, gpIIb/IIIa antagonist,anticoagulants, other compounds indicated for the treatment ofrheumatoid arthritis and formulations thereof.

[0040] In another embodiment, the invention provides a method oftreating a chemokine mediated disease, said disease being stroke andcardiac reperfusion injury comprising administering to a patient in needof such treatment an effective amount of one or more (e.g., one)compounds of formula (I) in combination (or association) with aneffective amount of one or more compounds selected from the groupconsisting of thrombolitics, antiplatelet agents, gpIIb/IIIa antagonist,and anticoagulants.

[0041] In another embodiment, the invention provides a method oftreating a chemokine mediated disease, said disease being stroke andcardiac reperfusion injury comprising administering to a patient in needof such treatment an effective amount of one or more (e.g., one)compounds of formula (I) in combination (or association) with aneffective amount of one or more compounds selected from the groupconsisting of an effective amount of one or more compounds selected fromthe group consisting of tenecteplase, TPA, alteplase, abciximab,eftiifbatide, heparin and formulations thereof.

[0042] This invention also provides novel compounds of formula (I),wherein said novel compounds are selected from the group consisting of:

[0043] or the pharmaceutically acceptable salts or solvates thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0044] Unless indicated otherwise, the following definitions applythroughout the present specification and claims. These definitions applyregardless of whether a term is used by itself or in combination withother terms. Hence the definition of “alkyl” applies to “alkyl” as wellas to the “alkyl” portions of “alkoxy”, etc.

[0045] When any variable (e.g., aryl, R²) occurs more than one time inany constituent, its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

[0046] “An effective amount” means a therapeutically effective amount,e.g., an amount that provides a clinical response to the disease beingtreated.

[0047] Examples of “one or more” include (a) 1, 2 or 3, (b) 1 or 2, or(c) 1.

[0048] Examples of “at least one” include (a) 1, 2 or 3, (b) 1 or 2, or(c) 1.

[0049] “Bn” represents benzyl.

[0050] “Alkyl” means a straight or branched saturated hydrocarbon chainhaving the designated number of carbon atoms. Where the number of carbonatoms is not specified, 1 to 20 carbons are intended. Preferred alkylgroups contain 1 to 12 carbon atoms in the chain. More preferred alkylgroups contain 1 to 6 carbon atoms in the chain.

[0051] “Alkoxy” means an alkyl-0 group in which alkyl is as previouslydefined. Non-limiting examples of alkoxy groups include methoxy, ethoxy,n-propoxy, iso-propoxy and n-butoxy. The bond to the parent moiety isthrough the ether oxygen.

[0052] “Alkenyl” means an aliphatic hydrocarbon group containing atleast one carbon-carbon double bond and which may be straight orbranched. Where the number of carbon atoms is not specified, 2 to 20carbons are intended. Preferred alkenyl groups have 2 to 12 carbon atomsin the chain; and more preferably 2 to 6 carbon atoms in the chain.Non-limiting examples of suitable alkenyl groups include ethenyl,propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl anddecenyl. Alkenylalkyl means that the alkenyl group is attached to theparent moiety through an alkyl group.

[0053] “Alkynyl” means an aliphatic hydrocarbon group containing atleast one carbon-carbon triple bond and which may be straight orbranched. Where the number of carbon atoms is not specified, 2 to 15carbons are intended. Preferred alkynyl groups have 2 to 12 carbon atomsin the chain; and more preferably 2 to 4 carbon atoms in the chain.Non-limiting examples of suitable alkynyl groups include ethynyl,propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.Alkynylalkyl means that the alkynyl group is attached to the parentmoiety through an alkyl group.

[0054] “Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. Non-limiting examples of suitable aryl groups includephenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl,fluorenyl and the like.

[0055] “Arylalkyl” means an aryl-alkyl group in which the aryl and alkylgroups are as defined. Non-limiting examples of suitable alkylarylgroups include o-tolyl, p-tolyl and xylyl. The bond to the parent moietyis through the alkyl group.

[0056] “Cycloalkyl” means a non-aromatic ring system having 3 to 10carbon atoms and one to three rings, preferably 5 to 10 carbon atoms.Preferred cycloalkyl rings contain 5 to 7 ring atoms. Non-limitingexamples of cycloalkyl groups include cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, norbornyl, adamantyl and the like.

[0057] “Cycloalkylalkyl” means a cycloalkyl group attached to the parentmoiety through an alkyl group. Non-limiting examples includecyclopropylmethyl, cyclohexylmethyl and the like.

[0058] “Cycloalkenyl” means a non-aromatic mono or multicyclic ringsystem comprising 3 to 10 carbon atoms, preferably 5 to 10 carbon atomswhich contains at least one carbon-carbon double bond. Preferredcycloalkenyl rings contain 5 to 7 ring atoms. Non-limiting examples ofcycloalkyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,norbornenyl and the like.

[0059] “Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

[0060] “Halogen” means fluorine, chlorine, bromine, or iodine. Preferredare fluorine, chlorine or bromine, and more preferred are fluorine andchlorine.

[0061] “Haloalkyl” means an alkyl group as defined above wherein one ormore hydrogen atoms on the alkyl is replaced by a halo group definedabove.

[0062] “Heterocyclyl” or “heterocyclic” means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising 3 to 10 ring atoms,preferably 5 to 10 ring atoms, in which one or more of the atoms in thering system is an element other than carbon, for example nitrogen,oxygen or sulfur, alone or in combination. There are no adjacent oxygenand/or sulfur atoms present in the ring system. Preferred heterocyclylscontain 5 to 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. The nitrogen or sulfur atomof the heterocyclyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitablemonocyclic heterocyclyl rings include piperidyl, pyrrolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like.

[0063] The term heterocyclic acidic functional group is intended toinclude groups such as, pyrrole, imidazole, triazole, tetrazole, and thelike.

[0064] “Heteroaryl” means an aromatic monocyclic or multicyclic ringsystem comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, inwhich one or more of the ring atoms is an element other than carbon, forexample nitrogen, oxygen or sulfur, alone or in combination. Preferredheteroaryls contain 5 to 6 ring atoms. The prefix aza, oxa or thiabefore the heteroaryl root name means that at least a nitrogen, oxygenor sulfur atom respectively, is present as a ring atom. A nitrogen atomof a heteroaryl can be optionally oxidized to the corresponding N-oxide.Non-limiting examples of suitable heteroaryls include pyridyl,pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl,oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl,triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

[0065] “Heteroarylalkyl” means a heteroaryl-alkyl group where the bondto the parent moiety is through an alkyl group.

[0066] N-oxides can form on a tertiary nitrogen present in an Rsubstituent, or on ═N— in a heteroaryl ring substituent and are includedin the compounds of formula I.

[0067] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

[0068] Compounds of formula (I) are described in WO 02/076926 publishedOct. 3, 2002, and WO 02/083624 published Oct. 24, 2002, the disclosuresof each being incorporated herein by reference thereto.

[0069] Examples of chemokine mediated diseases include: psoriasis,atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis,inflammatory bowel disease, Crohn's disease, ulcerative colitis, septicshock, endotoxic shock, gram negative sepsis, toxic shock syndrome,stroke, cardiac and renal reperfusion injury, glomerulonephritis,thrombosis, Alzheimer's disease, graft vs. host reaction, allograftrejections, malaria, acute respiratory distress syndrome, delayed typehypersensitivity reaction, atherosclerosis, cerebral and cardiacischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis,osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitisviruses, HIV (e.g., AIDS), Kaposi's sarcoma associated virus,meningitis, cystic fibrosis, pre-term labor, cough, pruritis,multi-organ dysfunction, trauma, strains, sprains, contusions, psoriaticarthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury,CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitialpneumonitis, hypersensitivity, crystal induced arthritis, acute andchronic pancreatitis, acute alcoholic hepatitis, necrotizingenterocolitis, chronic sinusitis, angiogenic ocular disease, ocularinflammation, retinopathy of prematurity, diabetic retinopathy, maculardegeneration with the wet type preferred and corneal neovascularization,polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiacdisease, esophagitis, glossitis, airflow obstruction, airwayhyperresponsiveness, bronchiectasis, bronchiolitis, bronchiolitisobliterans, chronic bronchitis, cor pulmonae, cough, dyspnea, emphysema,hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations,hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonaryhypertension, right ventricular hypertrophy, peritonitis associated withcontinuous ambulatory peritoneal dialysis (CAPD), granulocyticehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusionmismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burntherapy, periodontitis, transplant reperfusion injury and earlytransplantation.

[0070] Examples of anti-adhesion molecules include anti-CD11a(efalizumab), CD58-Fc (alefacept), anti-VLA (natalizumab), as well assmall molecule antagonists of LFA-1 (such as IC-747), VLA-4 (such asGW559090), and LFA-3. Examples of leukotriene inhibitors include LTD4receptor antagonists (e.g., Singulair), Zileuton, and inhibitors of5-lipoxygenase. Examples of inhibitors of cytokine production includeinhibitors of TNF-α such as thalidomide. Examples of other classes ofcompounds indicated for the treatment of rheumatoid arthritis includeinhibitors of p38 kinase, TNF-α converting enzyme (TACE), nitiric oxidesynthase and methotrexate.

[0071] For the compounds of formula (I):

[0072] A is selected from the group consisting of:

[0073] wherein the above rings of said A groups are substituted with 1to 6 substituents each independently selected from the group consistingof: R⁹ groups;

[0074] wherein one or both of the above rings of said A groups aresubstituted with 1 to 6 substituents each independently selected fromthe group consisting of: R⁹ groups;

[0075] wherein the above phenyl rings of said A groups are substitutedwith 1 to 3 substituents each independently selected from the groupconsisting of: R⁹ groups; and

[0076] B is selected from the group consisting of

[0077] n is 0 to 6;

[0078] p is 1 to 5;

[0079] X is 1 to 3;

[0080] R² is selected from the group consisting of: hydrogen, OH,—C(O)OH, —SH, —SO₂NR¹³R¹⁴, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —C(O)NHOR¹³, —C(O)NR¹³OH, —S(O₂)OH, —OC(O)R¹³,an unsubstituted heterocyclic acidic functional group, and a substitutedheterocyclic acidic functional group; wherein there are 1 to 6substituents on said substituted heterocyclic acidic functional groupeach substituent being independently selected from the group consistingof: R⁹ groups;

[0081] each R³ and R⁴ is independently selected from the groupconsisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF₃,—OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NHR¹⁷, —C(O)NR¹³R¹⁴,—SO_((t))NR¹³R¹⁴, —SO_((t))R¹³, —C(O)NR¹³OR¹⁴, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl,

[0082] wherein there are 1 to 6 substituents on said substituted arylgroup and each substituent is independently selected from the groupconsisting of: R⁹ groups; and wherein there are 1 to 6 substituents onsaid substituted heteroaryl group and each substituent is independentlyselected from the group consisting of: R⁹ groups;

[0083] each R⁵ and R⁶ are the same or different and are independentlyselected from the group consisting of hydrogen, halogen, alkyl, alkoxy,—CF₃, —OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴,—C(O)NR¹³OR¹⁴, cyano, unsubstituted or substituted aryl, andunsubstituted or substituted heteroaryl group; wherein there are 1 to 6substituents on said substituted aryl group and each substituent isindependently selected from the group consisting of: R⁹ groups; andwherein there are 1 to 6 substituents on said substituted heteroarylgroup and each substituent is independently selected from the groupconsisting of: R⁹ groups;

[0084] each R⁷ and R⁸ is independently selected from the groupconsisting of: H, unsubstituted or substituted alkyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴, alkynyl, alkenyl, andcycloalkenyl; and wherein there are one or more (e.g., 1 to 6)substituents on said substituted R⁷ and R⁸ groups, wherein eachsubstitutent is independently selected from the group consisting of:

[0085] a) halogen,

[0086] b) —CF₃,

[0087] c) —COR¹³,

[0088] d) —OR¹³,

[0089] e) —NR¹³R¹⁴

[0090] f) —NO₂,

[0091] g) —CN,

[0092] h) —SO₂OR¹⁴,

[0093] i) —Si(alkyl)₃, wherein each alkyl is independently selected,

[0094] j) —Si(aryl)₃, wherein each alkyl is independently selected,

[0095] k) —(R¹³)₂R¹⁴Si, wherein each R¹³ is independently selected,

[0096] l) —CO₂R¹³,

[0097] m) —C(O)NR³R¹⁴,

[0098] n) —SO₂NR¹³R¹⁴,

[0099] o) —SO₂R¹³,

[0100] p) —OC(O)R¹³,

[0101] q) —OC(O)NR¹³R¹⁴,

[0102] r) —NR¹³C(O)R¹⁴, and

[0103] s) —NR¹³CO₂R¹⁴;

[0104] (fluoroalkyl is one non-limiting example of an alkyl group thatis substituted with halogen);

[0105] R^(8a) is selected from the group consisting of: hydrogen, alkyl,cycloalkyl and cycloalkylalkyl;

[0106] each R⁹ is independently selected from the group consisting of:

[0107] a) —R¹³,

[0108] b) halogen,

[0109] c) —CF₃,

[0110] d) —COR¹³,

[0111] e) —OR¹³,

[0112] f) —NR¹³R¹⁴,

[0113] g) —NO₂,

[0114] h) —CN,

[0115] i) —SO₂R¹³,

[0116] j) —SO₂NR¹³R¹⁴,

[0117] k) —NR¹³COR¹⁴,

[0118] l) —CONR¹³R¹⁴,

[0119] m) —NR¹³CO₂R¹⁴,

[0120] n) —CO₂R¹³,

[0121] o)

[0122] p) alkyl substituted with one or more (e.g., one) —OH groups(e.g., —(CH₂)_(q)OH, wherein q is 1-6, usually 1 to 2, and preferably1),

[0123] q) alkyl substituted with one or more (e.g., one) —NR¹³R¹⁴ group(e.g., —(CH₂)_(q)NR¹³R¹⁴, wherein q is 1-6, usually 1 to 2, andpreferably 1), and

[0124] r) —N(R¹³)SO₂R¹⁴ (e.g., R¹³ is H and R¹⁴ is alkyl, such asmethyl);

[0125] each R¹⁰ and R¹¹ is independently selected from the groupconsisting of R¹³, (e.g., hydrogen and alkyl (e.g., C₁ to C₆ alkyl, suchas methyl)), halogen, —CF₃, —OCF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —OH,—C(O)OR¹³, —SH, —SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴,—NHSO₂R¹³, —C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³ and cyano;

[0126] R¹² is selected from the group consisting of: hydrogen,—C(O)OR¹³, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, unsubstituted or substituted arylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedalkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstitutedor substituted heteroarylalkyl group; wherein there are 1 to 6substituents on the substituted R¹² groups and each substituent isindependently selected from the group consisting of: R⁹ groups;

[0127] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, unsubstituted or substituted alkyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, unsubstituted or substituted heterocyclic,unsubstituted or substituted fluoroalkyl, and unsubstituted orsubstituted heterocycloalkylalkyl (wherein “heterocyloalkyl” meansheterocyclic); wherein there are 1 to 6 substituents on said substitutedR¹³ and R¹⁴ groups and each substituent is independently selected fromthe group consisting of: alkyl, —CF₃, —OH, alkoxy, aryl, arylalkyl,fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,—N(R⁴⁰)₂, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —S(O)_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵provided that R¹⁵ is not H, halogen, and —NHC(O)NR¹⁵R¹⁶; or

[0128] R¹³ and R¹⁴ taken together with the nitrogen they are attached toin the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted orsubstituted saturated heterocyclic ring (preferably a 3 to 7 memberedheterocyclic ring), said ring optionally containing one additionalheteroatom selected from the group consisting of: O, S and NR¹⁸; whereinthere are 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴groups (i.e., there is 1 to 3 substituents on the ring formed when theR¹³ and R¹⁴ groups are taken together with the nitrogen to which theyare bound) and each substituent is independently selected from the groupconsisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶,—C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶,—NHC(O)OR¹⁵, halogen, and a heterocycloalkenyl group (i.e., aheterocyclic group that has at least one, and preferably one, doublebond in a ring, e.g.,

[0129] each R¹⁵ and R¹⁶ is independently selected from the groupconsisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;

[0130] R¹⁷ is selected from the group consisting of: —SO₂alkyl,—SO₂aryl, —SO₂cycloalkyl, and —SO₂heteroaryl;

[0131] R¹⁸ is selected from the group consisting of: H, alkyl, aryl,heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰;

[0132] each R¹⁹ and R²⁰ is independently selected from the groupconsisting of: alkyl, aryl and heteroaryl;

[0133] R³⁰ is selected from the group consisting of: alkyl, cycloalkyl,—CN, —NO₂, or —SO₂R¹⁵ provided that R¹⁵ is not H;

[0134] each R³¹ is independently selected from the group consisting of:unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl and unsubstituted or substituted cycloalkyl;wherein there are 1 to 6 substituents on said substituted R³¹ groups andeach substituent is independently selected from the group consisting of:alkyl, halogen and —CF₃;

[0135] each R⁴⁰ is independently selected from the group consisting of:H, alkyl and cycloalkyl;

[0136] g is 1 or 2; and

[0137] t is 0, 1 or 2.

[0138] For compounds of formula (I), when R³ is —SO_((t))NR¹³R¹⁴ (e.g.,—SO₂NR¹³R¹⁴), preferably R¹³ and R¹⁴ are independently selected from thegroup consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl andt-butyl). Examples include, but are not limited to (1) —SO₂NH₂ and (2)—SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ are the same or different alkyl group(e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkylgroup, such as, for example —SO₂N(CH₃)₂.

[0139] For compounds of formula (I), when R³ is —C(O)NR¹³R¹⁴, preferablyR¹³ and R¹⁴ are independently selected from the group consisting of: Hand alkyl (e.g., methyl, ethyl, isopropyl and t-butyl). Examplesinclude, but are not limited to —C(O)NR¹³R¹⁴ wherein each R¹³ and R¹⁴are the same or different alkyl group, e.g., the same alkyl group, suchas, for example —C(O)N(CH₃)₂.

[0140] For the compounds of formula (I) substituent A is preferablyselected from the group consisting of:

[0141] (1) unsubstituted or substituted:

[0142] wherein all substitutents are as defined for formula (I).

[0143] Examples of substituent A in formula (I) include, but are notlimited to:

[0144] Substituent A in formula (I) is most preferably selected from thegroup consisting of:

[0145] Substituent A in formula (I) is more preferably selected from thegroup consisting of:

[0146] Substituent B in formula (I) is preferably selected from thegroup consisting of:

[0147] wherein all substituents are as defined for formula (I).

[0148] Substituent B in formula (I) is most preferably selected from thegroup consisting of:

[0149] Substituent B in Formula (I) is more preferably selected from thegroup consisting of:

[0150] Compounds of formula (I) useful in the methods of this inventionare described in the embodiments below. The embodiments have beennumbered for purposes of reference thereto.

[0151] Embodiment No. 1 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0152] and all other substitutents are as defined for of formula (I).

[0153] Embodiment No. 2 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0154] and all other substitutents are as defined for of formula (I).

[0155] Embodiment No. 3 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0156] and all other substitutents are as defined for of formula (I).

[0157] Embodiment No. 4 is is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0158] and all other substitutents are as defined for of formula (I).

[0159] Embodiment No. 5 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0160] and all other substitutents are as defined for of formula (I).

[0161] Embodiment No. 6 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0162] and all other substitutents are as defined for of formula (I).

[0163] Embodiment No. 7 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0164] and all other substitutents are as defined for of formula (I).

[0165] Embodiment No. 8 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0166] and all other substitutents are as defined for of formula (I).

[0167] Embodiment No. 9 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0168] and all other substitutents are as defined for of formula (I).

[0169] Embodiment No. 10 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0170] and all other substitutents are as defined for of formula (I).

[0171] Embodiment No. 11 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0172] and all other substitutents are as defined for of formula (I).

[0173] Embodiment No. 12 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0174] and all other substitutents are as defined for of formula (I).

[0175] Embodiment No. 13 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0176] and all other substitutents are as defined for of formula (I).

[0177] Embodiment No. 14 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0178] and all other substitutents are as defined for of formula (I).

[0179] Embodiment No. 15 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0180] and all other substitutents are as defined for of formula (I).

[0181] Embodiment No. 16 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0182] and all other substitutents are as defined for of formula (I).

[0183] Embodiment No. 17 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0184] and all other substitutents are as defined for of formula (I).

[0185] Embodiment No. 18 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0186] and all other substitutents are as defined for of formula (I).

[0187] Embodiment No. 19 is directed to the methods of this inventionusing compounds of formula (I) wherein B is selected from the groupconsisting of:

[0188] and R³ for this B group is selected from the group consisting of:—C(O)NR¹³R¹⁴,

[0189] and all other substituents are as defined for formula (I).

[0190] Embodiment No. 20 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0191] and all other substituents are as defined in formula (I).

[0192] Embodiment No. 21 is directed to the methods of this inventionusing compounds of formula (I) wherein B is

[0193] R¹³ and R¹⁴ are independently selected from the group consistingof H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), and allother substituents are as defined in formula (I).

[0194] Embodiment No. 22 is directed to the methods of this inventionusing compounds of formula (I) wherein B is

[0195] wherein:

[0196] (1) R² is —OH and all other substituents are as defined informula (I), or

[0197] (2) R² is —OH, and R¹³ and R¹⁴ are independently selected fromthe group, consisting of: H and alkyl (e.g., methyl, ethyl, isopropyland t-butyl), or

[0198] (3) R² is —OH, and R¹³ and R¹⁴ are the same or different andalkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), for examplethe same alkyl group, for example methyl, and

[0199] (4) and all other substituents are as defined in formula (I).

[0200] Embodiment No. 23 is directed to the methods of this inventionusing compounds of formula (I) wherein B is

[0201] R³ is selected from the group consisting of:

[0202] and all other substituents are as defined in formula (I).

[0203] Embodiment No. 24 is directed to the methods of this inventionusing compounds of formula (I) wherein B is

[0204] R³ is selected from the group consisting of:

[0205] R² is —OH, and all other substituents are as defined in formula(I).

[0206] Embodiment No. 25 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0207] and all other substituents are as defined in formula (I)

[0208] Embodiment No. 26 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0209] R² is —OH, and all other substituents are as defined in formula(I).

[0210] Embodiment No. 27 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0211] R² is as defined for compounds of formula (I), R¹³ and R¹⁴ areindependently selected from the group consisting of H and alkyl (e.g.,methyl, ethyl, isopropyl and t-butyl), and all other substituents areasdefined for compounds of formula (I). For example, R¹³ and R¹⁴ are thesame or different alkyl group. Also, for example, R¹³ and R¹⁴ are thesame alkyl group. Also, for example, R¹³ and R¹⁴ are methyl.

[0212] Embodiment No. 28 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0213] R² is —OH, R¹³ and R¹⁴ are independently selected from the groupconsisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl),and all other substituents areas defined for compounds of formula (I).For example, R¹³ and R¹⁴ are the same or different alkyl group. Also,for example, R¹³ and R¹⁴ are the same alkyl group. Also, for example,R¹³ and R¹⁴ are methyl.

[0214] Embodiment No. 29 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in EmbodimentNo. 23, R⁴ is H, R⁵ is H, R⁶ is H, and all other substituents are asdefined for compounds of formula (I).

[0215] Embodiment No. 30 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in EmbodimentNo. 24, R⁴ is H, R⁵ is H, R⁶ is H, and all other substituents areasdefined for compounds of formula (I).

[0216] Embodiment No. 31 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in EmbodimentsNos. 21, 22, 25 and 26, except that R¹³ and R¹⁴ are each methyl, and allother substituents are as defined in formula (I).

[0217] Embodiment No. 32 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0218] R¹¹ is H, and all other substituents are as defined in formula(I).

[0219] Embodiment No. 33 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0220] R² is —OH, and all other substituents are as defined in formula(I).

[0221] Embodiment No. 34 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0222] R³ is —C(O)NR¹³R¹⁴, and all other substituents are as defined informula (I).

[0223] Embodiment No. 35 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0224] R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all other substituentsare as defined in formula (I).

[0225] Embodiment No. 36 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0226] R² is —OH, R³ is —C(O)NR¹³R¹⁴, and all other substituents are asdefined in formula (I).

[0227] Embodiment No. 37 of this invention is directed to the methods ofthis invention using compounds of formula (I) wherein B is:

[0228] R² is —OH, and R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and allother substituents are as defined in formula (I).

[0229] Embodiment No. 38 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0230] R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H, and all othersubstituents are as defined in formula (I).

[0231] Embodiment No. 39 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0232] R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, andall other substituents are as defined in formula (I).

[0233] Embodiment No. 40 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0234] R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H, and R¹³ and R¹⁴ areindependently selected from the group consisting of: H, alkyl (e.g.,methyl, ethyl, isopropyl and t-butyl), unsubstituted heteroaryl andsubstituted heteroaryl, and all other substituents are as defined informula (I). For example, one of R¹³ or R¹⁴ is alkyl (e.g., methyl). Anexample of a substituted heteroaryl group is

[0235] Embodiment No. 41 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0236] R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, andR¹³ and R¹⁴ are independently selected from the group consisting of: Hand alkyl (e.g., methyl, ethyl, isopropyl, and t-butyl), and all othersubstituents are as defined in formula (I). For example R³ is (1)—SO₂NH₂ and (2) —SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ are the same ordifferent alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl),e.g., the same alkyl group, such as, for example —SO₂N(CH₃)₂.

[0237] Embodiment No. 42 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0238] R¹¹ is H, and all other substituents are as defined in formula(I).

[0239] Embodiment No. 43 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0240] R² is —OH, and all other substituents are as defined in formula(I).

[0241] Embodiment No. 44 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0242] R³ is —C(O)NR¹³R¹⁴, and all other substituents are as defined informula (I).

[0243] Embodiment No. 45 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0244] R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all other substituentsare as defined in formula (I).

[0245] Embodiment No. 46 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0246] R² is —OH, R³ is —C(O)NR¹³R¹⁴, and all other substituents are asdefined in formula (I).

[0247] Embodiment No. 47 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0248] R² is —OH, and R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and allother substituents are as defined in formula (I).

[0249] Embodiment No. 48 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0250] R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H, and all othersubstituents are as defined in formula (I).

[0251] Embodiment No. 49 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0252] R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, andall other substituents are as defined in formula (I).

[0253] Embodiment No. 50 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0254] R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H, and R¹³ and R¹⁴ areindependently selected from the group consisting of: alkyl,unsubstituted heteroaryl and substituted heteroaryl, and all othersubstituents are as defined in formula (I). For example, one of R¹³ orR¹⁴ is alkyl (e.g., methyl). An example of a substituted heteroarylgroup is

[0255] Embodiment No. 51 is directed to the methods of this inventionusing compounds of formula (I) wherein B is:

[0256] R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, R¹³and R¹⁴ are independently selected from the group consisting of: H andalkyl (e.g., methyl, ethyl, isopropyl, and tbutyl), and all othersubstituents are as defined in formula (I). For example R³ is (1)—SO₂NH₂ and (2) —SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ are the same ordifferent alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl),e.g., the same alkyl group, such as, for example —SO₂N(CH₃)₂.

[0257] Embodiment No. 52 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent B is selected fromthe group consisting of:

[0258] wherein R² to R⁶ and R¹⁰ to R¹⁴ are as defined above for thecompounds of formula (I).

[0259] Embodiment No. 53 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent B is selected fromthe group consisting of:

[0260] wherein

[0261] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ orand —NHSO₂R¹³;

[0262] R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴, —NO₂,cyano, —C(O)NR¹³R¹⁴, —SO₂R¹³; and —C(O)OR¹³;

[0263] R⁴ is selected from the group consisting of: H, —NO₂, cyano,—CH₃, halogen, and —CF₃;

[0264] R⁵ is selected from the group consisting of: H, —CF₃, —NO₂,halogen and cyano;

[0265] R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

[0266] each R¹⁰ and R¹¹ is independently selected from the groupconsisting of: R¹³, hydrogen, halogen, —CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴,—C(O)OR¹³, —SH, —SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴,—NHSO₂R¹³, —C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³, —COR¹³, —OR¹³, andcyano;

[0267] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl, ethyl and isopropyl; or

[0268] R¹³ and R¹⁴ when taken together with the nitrogen they areattached to in the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴,—OC(O)NR¹³R¹⁴, —CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴,—NHSO₂NR¹³R¹⁴ form an unsubstituted or substituted saturatedheterocyclic ring (preferably a 3 to 7 membered ring) optionally havingone additional heteroatom selected from the group consisting of: O, S orNR¹⁸; wherein R¹⁸ is selected from the group consisting of: H, alkyl,aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰; wherein each R¹⁹and R²⁰ is independently selected from the group consisting of: alkyl,aryl and heteroaryl; wherein there are 1 to 3 substituents on thesubstituted cyclized R¹³ and R¹⁴ groups (i.e., the substituents on thering formed when R¹³ and R¹⁴ are taken together with the nitrogen towhich they are bound) and each substituent is independently selectedfrom the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl,alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵,—C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is notH, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ isindependently selected from the group consisting: of H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

[0269] Embodiment No. 54 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent B is selected fromthe group consisting of: R⁵

[0270] wherein:

[0271] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³;

[0272] R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴,—SO₂NR¹³R¹⁴, —NO₂, cyano, —SO₂R¹³; and —C(O)OR¹³;

[0273] R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃or —CF₃;

[0274] R⁵ is selected from the group consisting of: H, —CF₃, —NO₂,halogen and cyano; and

[0275] R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

[0276] R¹¹ is selected from the group consisting of: H, halogen andalkyl; and

[0277] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl, ethyl and isopropyl; or

[0278] R¹³ and R¹⁴ when taken together with the nitrogen they areattached to in the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴,—OC(O)NR¹³R¹⁴, —CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴,—NHSO₂NR¹³R¹⁴ form an unsubstituted or substituted saturatedheterocyclic ring (preferably a 3 to 7 membered ring) optionally havingone additional heteroatom selected from O, S or NR¹⁸ wherein R¹⁸ isselected from H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and—C(O)NR¹⁹R²⁰, wherein each R¹⁹ and R²⁰ is independently selected fromalkyl, aryl and heteroaryl, wherein there are 1 to 3 substituents on thesubstituted cyclized R¹³ and R¹⁴ groups (i.e., on the ring formed whenR¹³ and R¹⁴ are taken together with the nitrogen to which they arebound) and each substituent is independently selected from the groupconsisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶,—C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ andhalogen; and wherein each R¹⁵ and R¹⁶ is independently selected from thegroup consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl andheteroaryl.

[0279] Embodiment No. 55 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent B is selected fromthe group consisting of:

[0280] wherein:

[0281] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³;

[0282] R³ is selected from the group consisting of:—C(O)NR¹³R¹⁴—SO₂NR¹³R¹⁴, —NO₂, cyano, and —SO₂R¹³;

[0283] R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃or —CF₃;

[0284] R⁵ is selected from the group consisting of: H, —CF₃, —NO₂,halogen and cyano; and

[0285] R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

[0286] R¹¹ is selected from the group consisting of: H, halogen andalkyl; and

[0287] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl and ethyl.

[0288] Embodiment No. 56 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent B is selected fromthe group consisting of:

[0289] wherein:

[0290] R² is —OH;

[0291] R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴ and—CONR¹³R¹⁴;

[0292] R⁴ is selected form the group consisting of: H, —CH₃ and —CF₃;

[0293] R⁵ is selected from the group consisting of: H and cyano;

[0294] R⁶ is selected from the group consisting of: H, —CH₃ and —CF₃;

[0295] R¹¹ is H; and

[0296] R¹³ and R¹⁴ are independently selected from the group consistingof H and methyl (e.g., for —SO₂NR¹³R¹⁴ both R¹³ and R¹⁴ are H, or bothR¹³ and R¹⁴ are methyl, also, for example, for —CONR¹³R¹⁴ both R¹³ andR¹⁴ are methyl).

[0297] Embodiment No. 57 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent B is selected fromthe group consisting of:

[0298] wherein all substituents are as defined for formula (I).

[0299] Embodiment No. 58 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent B is selected fromthe group consisting of:

[0300] Embodiment No. 59 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent B is selected fromthe group consisting of:

[0301] Embodiment No. 60 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is selected fromthe group consisting of:

[0302] wherein the above rings are unsubstituted or substituted, asdescribed for formula (I); and

[0303] wherein in (a) and (b): each R⁷ and R⁸ is independently selectedfrom the group consisting of: H, unsubstituted or substituted alkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein saidsubstituents on said R⁷ and R⁸ substituted groups are selected from thegroup consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d)—SO₂NR¹³R¹⁴, e) —NO₂, f) —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j)—OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined informula (I).

[0304] Embodiment No. 61 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is selected fromthe group consisting of:

[0305] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and—NO₂; each R⁷ and R⁸ is independently selected from the group consistingof: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl(such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, andcyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R⁹ isselected from the group consisting of: H, halogen, alkyl, cycloalkyl,—CF₃, cyano, —OCH₃, and —NO₂; and

[0306] wherein each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); whereinR⁸, is as defined in formula (I), and wherein R⁹ is selected from thegroup consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃,and —NO₂; each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl).

[0307] Embodiment No. 62 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is selected fromthe group consisting of:

[0308] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, fluoroalkyl, alkyl andcycloalkyl; R⁸ is selected form the group consisting of: H, alkyl,—CF₂CH₃ and —CF₃; and R⁹ is selected from the group consisting of: H, F,Cl, Br, alkyl or —CF₃; and

[0309] wherein R⁷ is selected from the group consisting of: H,fluoroalkyl, alkyl and cycloalkyl; R⁸ is selected form the groupconsisting of: H, alkyl, —CF₂CH₃ and —CF₃; and R^(8a) is as defined forformula (I).

[0310] Embodiment No. 63 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is selected fromthe group consisting of:

[0311] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

[0312] wherein R⁷ is selected from the group consisting of: H, —CF₃,—CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H;and R^(8a) is as defined for formula (I).

[0313] Embodiment No. 64 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is selected fromthe group consisting of:

[0314] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

[0315] wherein R⁷ is selected from the group consisting of: H, —CF₃,—CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H;and R^(8a) is as defined for formula IA;

[0316] Embodiment No. 65 is directed compounds of formula (1) whereinsubstituent A is selected from the group consisting of:

[0317] (1) unsubstituted or substituted:

[0318] wherein all substitutents are as defined for formula (I).

[0319] Embodiment No. 66 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is selected fromthe group consisting of:

[0320] Embodiment No. 67 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is selected fromthe group consisting of:

[0321] Embodiment No. 68 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is selected fromthe group consisting of:

[0322] Embodiment No. 69 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in any one ofthe Embodiment Nos. 1 to 59, and A is as defined in any one of theEmbodiment Nos. 60 to 68.

[0323] Embodiment No. 70 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in any one ofthe Embodiment Nos. 1 to 59, and A is:

[0324] and all other substituents are as defined for formula (I).

[0325] Embodiment No. 71 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in any one ofthe Embodiment Nos. 1 to 59, and A is:

[0326] wherein R⁷ is H, and R⁸ is alkyl (e.g., methyl, ethyl, isopropyl,cyclopropyl and t-butyl), and all other substituents are as defined forformula (I).

[0327] Embodiment No. 72 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in any one ofthe Embodiment Nos. 1 to 59, and A is:

[0328] and all other substituents are as defined for formula (I).

[0329] Embodiment No. 73 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in any one ofthe Embodiment Nos. 1 to 59, and A is:

[0330] wherein the furan ring is unsubstituted or substituted asdescribed in the definition of A for formula (I), and all othersubstituents are as defined for formula (I).

[0331] Embodiment No. 74 is directed to the methods of this inventionusing compounds of formula (I) wherein B is described in any one of theEmbodiment Nos. 1 to 59, and A is

[0332] wherein the furan ring is substituted and all other substituentsare as defined for formula (I).

[0333] Embodiment No. 75 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in any one ofthe Embodiment Nos. 1 to 59, and A is

[0334] wherein the furan ring is substituted with at least one (e.g., 1to 3, or 1 to 2) alkyl group and all other substituents are as definedfor formula (I).

[0335] Embodiment No. 76 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in any one ofthe Embodiment Nos. 1 to 59, A is

[0336] wherein the furan ring is substituted with one alkyl group andall other substituents are as defined for formula (I).

[0337] Embodiment No. 77 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in any one ofthe Embodiment Nos. 1 to 59, and A is

[0338] wherein the furan ring is substituted with one C₁ to C₃ alkylgroup (e.g., methyl or isopropyl), and all other substituents are asdefined for formula (I).

[0339] Embodiment No. 78 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in any one ofthe Embodiment Nos. 1 to 59, and A is as defined in any one of theEmbodiment Nos. 73 to 77, except that R⁷ and R⁸ are the same ordifferent and each is selected from the group consisting of: H andalkyl.

[0340] Embodiment No. 79 is directed to the methods of this inventionusing compounds of formula (I) wherein B is as described in any one ofthe Embodiment Nos. 1 to 59, and A is as defined in any one of theEmbodiment Nos. 73 to 77, except that R⁷ is H, and R⁸ is alkyl (e.g.,ethyl or t-butyl).

[0341] Embodiment No. 80 is directed to the methods of this inventionusing compounds of formula (I) wherein:

[0342] (1) substituent A in formula (I) is selected from the groupconsisting of:

[0343] wherein the above rings are unsubstituted or substituted, asdescribed for formula (I); and

[0344] wherein in (a) and (b) above: each R⁷ and R⁸ is independentlyselected from the group consisting of: H, unsubstituted or substitutedalkyl, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein saidsubstituents on said R⁷ and R⁸ substituted groups are selected from thegroup consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d)—SO₂NR¹³R¹⁴, e) —NO₂, f) —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j)—OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined informula (I); and

[0345] (2) substituent B in formula (I) is selected from the groupconsisting of:

[0346] wherein R² to R⁶ and R¹⁰ to R¹⁴ are as defined above for thecompounds of formula (I).

[0347] Embodiment No. 81 is directed to the methods of this inventionusing compounds of formula (I) wherein:

[0348] (1) substituent A in formula (I) is selected from the groupconsisting of:

[0349] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and—NO₂; each R⁷ and R⁸ is independently selected from the group consistingof: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl(such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, andcyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R⁹ isselected from the group consisting of: H, halogen, alkyl, cycloalkyl,—CF₃, cyano, —OCH₃, and —NO₂; and

[0350] wherein each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); whereinR^(8a) is as defined in formula (1), and wherein R⁹ is selected from thegroup consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃,and —NO₂; each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and

[0351] (2) substituent B in formula (I) is selected from the groupconsisting of:

[0352] wherein

[0353] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ orand —NHSO₂R¹³;

[0354] R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴, —NO₂,cyano, —C(O)NR¹³R¹⁴, —SO₂R¹³; and —C(O)OR¹³;

[0355] R⁴ is selected from the group consisting of: H, —NO₂, cyano,—CH₃, halogen, and —CF₃;

[0356] R⁵ is selected from the group consisting of: H, —CF₃, —NO₂,halogen and cyano;

[0357] R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

[0358] each R¹⁰ and R¹¹ is independently selected from the groupconsisting of: R¹³, hydrogen, halogen, —CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴,—C(O)OR¹³, —SH, —SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴,—NHSO₂R¹³, —C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³, —COR¹³, —OR¹³, andcyano;

[0359] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl, ethyl and isopropyl; or

[0360] R¹³ and R¹⁴ when taken together with the nitrogen they areattached to in the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴,—OC(O)NR¹³R¹⁴, —CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴,—NHSO₂NR¹³R¹⁴ form an unsubstituted or substituted saturatedheterocyclic ring (preferably a 3 to 7 membered ring) optionally havingone additional heteroatom selected from the group consisting of: O, S orNR¹⁸; wherein R¹⁸ is selected from the group consisting of: H, alkyl,aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰; wherein each R¹⁹and R²⁰ is independently selected from the group consisting of: alkyl,aryl and heteroaryl; wherein there are 1 to 3 substituents on thesubstituted cyclized R¹³ and R¹⁴ groups (i.e., the substituents on thering formed when R¹³ and R¹⁴ are taken together with the nitrogen towhich they are bound) and each substituent is independently selectedfrom the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl,alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵,—C(O)NR¹⁵R¹⁶—SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵—SO₂R¹⁵ provided that R¹⁵ is not H,—NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ isindependently selected from the group consisting: of H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

[0361] Embodiment No. 82 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is even morepreferably selected from the group consisting of:

[0362] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, fluoroalkyl, alkyl andcycloalkyl; R⁸ is selected form the group consisting of: H, alkyl,—CF₂CH₃ and —CF₃; and R⁹ is selected from the group consisting of: H, F,Cl, Br, alkyl or —CF₃; and

[0363] wherein R⁷ is selected from the group consisting of: H,fluoroalkyl, alkyl and cycloalkyl; R⁸ is selected form the groupconsisting of: H, alkyl, —CF₂CH₃ and —CF₃; and R^(8a) is as defined forformula (1).

[0364] Embodiment No. 83 is directed to the methods of this inventionusing compounds of formula (1) wherein:

[0365] (1) substituent A is selected from the group consisting of:

[0366] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

[0367] wherein R⁷ is selected from the group consisting of: H, —CF₃,—CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H;and R^(8a) is as defined for formula (I); and

[0368] (2) substituent B is selected from the group consisting of:

[0369] wherein:

[0370] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³;

[0371] R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴,—SO₂NR¹³R¹⁴, —NO₂, cyano, —SO₂R¹³; and —C(O)OR¹³;

[0372] R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃or —CF₃;

[0373] R⁵ is selected from the group consisting of: H, —CF₃, —NO₂,halogen and cyano; and

[0374] R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

[0375] R¹¹ is selected from the group consisting of: H, halogen andalkyl; and

[0376] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl, ethyl and isopropyl; or

[0377] R¹³ and R¹⁴ when taken together with the nitrogen they areattached to in the groups —NR¹³R⁴, —C(O)NR¹³R¹⁴, —SO₂NR³R⁴, —QC(O)NR³R⁴,—CONR³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴, —NHSO₂NR¹³R¹⁴ form anunsubstituted or substituted saturated heterocyclic ring (preferably a 3to 7 membered ring) optionally having one additional heteroatom selectedfrom O, S or NR¹⁸ wherein R¹⁸ is selected from H, alkyl, aryl,heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰, wherein each R¹⁹ and R²⁰is independently selected from alkyl, aryl and heteroaryl, wherein thereare 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., on the ring formed when R¹³ and R¹⁴ are taken together with thenitrogen to which they are bound) and each substituent is independentlyselected from the group consisting of: alkyl, aryl, hydroxy,hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵,—C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is notH, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ isindependently selected from the group consisting of: H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

[0378] Embodiment No. 84 is directed to the methods of this inventionusing compounds of formula (I) wherein:

[0379] (1) substituent A is selected from the group consisting of:

[0380] wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

[0381] wherein R⁷ is selected from the group consisting of: H, —CF₃,—CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H;and R^(8a) is as defined for formula (I);

[0382] (2) substituent B is selected from the group consisting of:

[0383] wherein:

[0384] R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³;

[0385] R³ is selected from the group consisting of:—C(O)NR¹³R¹⁴—SO₂NR¹³R¹⁴, —NO₂, cyano, and —SO₂R¹³;

[0386] R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃or —CF₃;

[0387] R⁵ is selected from the group consisting of: H, —CF₃, —NO₂,halogen and cyano; and

[0388] R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

[0389] R¹¹ is selected from the group consisting of: H, halogen andalkyl; and

[0390] each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, methyl and ethyl.

[0391] Embodiment No. 85 is directed to the methods of this inventionusing compounds of formula (I) wherein:

[0392] (1) substituent A is selected from the group consisting of:

[0393] (2) substituent B is selected from the group consisting of:

[0394] wherein:

[0395] R² is —OH;

[0396] R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴ and—CONR¹³R¹⁴;

[0397] R⁴ is selected form the group consisting of: H, —CH₃ and —CF₃;

[0398] R⁵ is selected from the group consisting of: H and cyano;

[0399] R⁶ is selected from the group consisting of: H, —CH₃ and —CF₃;

[0400] R¹¹ is H; and

[0401] R¹³ and R¹⁴ are independently selected from the group consistingof H and methyl (e.g., for —SO₂NR¹³R¹⁴ both R¹³ and R¹⁴ are H, or bothR¹³ and R¹⁴ are methyl, also, for example, for —CONR¹³R¹⁴ both R¹³ andR¹⁴ are methyl).

[0402] Embodiment No. 86 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is as defined inEmbodiment No. 65 and substituent B is as defined in Embodiment No. 57.

[0403] Embodiment No. 87 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is as defined inEmbodiment No. 65 and substituent B is as defined in Embodiment No. 58.

[0404] Embodiment No. 88 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is as defined inEmbodiment No. 65 and substituent B is as defined in Embodiment No. 59.

[0405] Embodiment No. 89 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is as defined inEmbodiment No. 66 and substituent B is as defined in Embodiment No. 57.

[0406] Embodiment No. 90 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is as defined inEmbodiment No. 66 and substituent B is as defined in Embodiment No. 58.

[0407] Embodiment No. 91 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is as defined inEmbodiment No. 66 and substituent B is as defined in Embodiment No. 59.

[0408] Embodiment No. 92 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is as defined inEmbodiment No. 67 and substituent B is as defined in Embodiment No. 57.

[0409] Embodiment No. 93 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is as defined inEmbodiment No. 67 and substituent B is as defined in Embodiment No. 58.

[0410] Embodiment No. 94 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is as defined inEmbodiment No. 67 and substituent B is as defined in Embodiment No. 59.

[0411] Embodiment No. 95 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is as defined inEmbodiment No. 68 and substituent B is as defined in Embodiment No. 57.

[0412] Embodiment No. 96 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is as defined inEmbodiment No. 68 and substituent B is as defined in Embodiment No. 58.

[0413] Embodiment No. 97 is directed to the methods of this inventionusing compounds of formula (I) wherein substituent A is as defined inEmbodiment No. 68 and substituent B is as defined in Embodiment No. 59.

[0414] Embodiment No. 98 is directed to the methods of this inventionusing compounds of formula (I) as defined in any one of the EmbodimentNos. 1 to 97 wherein the compound of formula (I) is a pharmaceuticallyacceptable salt.

[0415] Embodiment No. 99 is directed to the methods of this inventionusing compounds of formula (I) as defined in any one of the EmbodimentNos. 1 to 97 wherein the compound of formula (I) is a sodium salt.

[0416] Embodiment No. 100 is directed to the methods of this inventionusing compounds of formula (I) as defined in any one of the EmbodimentNos. 1 to 97 wherein the compound of formula (I) is a calcium salt.

[0417] Embodiment No. 101 is directed to the methods of this inventionusing a pharmaceutically acceptable salt of any one of therepresentative compounds of formula (I) described below.

[0418] Embodiment No. 102 is directed to the methods of this inventionusing a sodium salt of any one of the representative compounds offormula (I) described below.

[0419] Embodiment No. 103 is directed to the methods of this inventionusing a calcium salt of any one of the representative compounds offormula (I) described below.

[0420] Embodiment No. 104 is directed to the methods of this inventionusing a pharmaceutical composition comprising at least one (e.g., 1 to3, usually 1) compound of formula (I) as described in any one of theEmbodiment Nos. 1 to 103 in combination with a pharmaceuticallyacceptable carrier (or diluent).

[0421] Embodiment No. 105 is directed to a pharmaceutically acceptablesalt of a novel compound of formula (I), wherein said compound isselected from the group consisting of:

[0422] Embodiment No. 106 is directed to a calcium salt of any one ofthe novel compounds of formula (I) described in Embodiment No. 105.

[0423] Embodiment No. 107 is directed to a sodium salt of any one of thenovel compounds of formula (I) described in Embodiment No. 105.

[0424] Embodiment No. 108 is directed to a pharmaceutical compositioncomprising at least one (e.g., 1 to 3, usually 1) novel compound offormula (I) as described in Embodiment No. 105 in combination with apharmaceutically acceptable carrier (or diluent).

[0425] Representative compounds of formula (I) useful in the methods ofthis invention include but are not limited to:

[0426] Preferred compounds of formula (I) useful in the methods of thisinvention include:

[0427] A more preferred group of compounds of formula (I) useful in themethods of this invention include:

[0428] A most preferred group of compounds of formula (I) useful in themethods of this invention include:

[0429] Certain compounds of formula (I) may exist in differentstereoisomeric forms (e.g., enantiomers, diastereoisomers andatropisomers). The invention contemplates all such stereoisomers both inpure form and in admixture, including racemic mixtures. Isomers can beprepared using conventional methods.

[0430] Certain compounds will be acidic in nature, e.g. those compoundswhich possess a carboxyl or phenolic hydroxyl group. These compounds mayform pharmaceutically acceptable salts. Examples of such salts mayinclude sodium, potassium, calcium, aluminum, gold and silver salts.Also contemplated are salts formed with pharmaceutically acceptableamines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

[0431] Certain basic compounds also form pharmaceutically acceptablesalts, e.g., acid addition salts. For example, the pyrido-nitrogen atomsmay form salts with strong acid, while compounds having basicsubstituents such as amino groups also form salts with weaker acids.Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineraland carboxylic acids well known to those skilled in the art. The saltsare prepared by contacting the free base form with a sufficient amountof the desired acid to produce a salt in the conventional manner. Thefree base forms may be regenerated by treating the salt with a suitabledilute aqueous base solution such as dilute aqueous NaOH, potassiumcarbonate, ammonia and sodium bicarbonate. The free base forms differfrom their respective salt forms somewhat in certain physicalproperties, such as solubility in polar solvents, but the acid and basesalts are otherwise equivalent to their respective free base forms forpurposes of the invention.

[0432] All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

[0433] Compounds of formula (I) can exist in unsolvated and solvatedforms, including hydrated forms. In general, the solvated forms, withpharmaceutically acceptable solvents such as water, ethanol and thelike, are equivalent to the unsolvated forms for the purposes of thisinvention.

[0434] This invention also includes Prodrugs of the novel compounds ofthis invention, and of the compounds of formula (I) useful in themethods of this invention. The term “prodrug,” as used herein,represents compounds which are rapidly transformed in vivo to the parentcompound of the above formula, for example, by hydrolysis in blood. Athorough discussion is provided in T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, andin Edward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference.

[0435] For preparing pharmaceutical compositions from the compounds offormula (I), inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets and suppositories. The powdersand tablets may be comprised of from about 5 to about 95 percent activeingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington: The Science and Practice ofPharmacy, 20^(th) Edition, (2000), Lippincott Williams & Wilkins,Baltimore, Md.

[0436] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

[0437] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

[0438] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0439] The compounds of formula (I) may also be deliverabletransdermally. The transdermal composition can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

[0440] Preferably the compound of formula (I) is administered orally.

[0441] Preferably, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active component,e.g., an effective amount to achieve the desired purpose.

[0442] The quantity of active compound in a unit dose of preparation maybe varied or adjusted from about 0.01 mg to about 1000 mg, preferablyfrom about 0.01 mg to about 750 mg, more preferably from about 0.01 mgto about 500 mg, and most preferably from about 0.01 mg to about 250 mg,according to the particular application.

[0443] The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage regimen for a particularsituation is within the skill of the art. For convenience, the totaldosage may be divided and administered in portions during the day asrequired.

[0444] The amount and frequency of administration of the compounds offormula (I) and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 0.04mg/day to about 4000 mg/day, in two to four divided doses.

[0445] The compounds used in combination with the compounds of formula(I) can be administered in their normally prescribed amounts as know bythe skilled clinician (see, for example, the Physicians' Desk Reference,56^(th) edition, 2002, published by Medical Economics company, Inc. atMontvale, NJ 07645-1742, the disclosure of which is incorporated hereinby reference thereto). The amount and frequency of administration of thecompounds used in combination with the compounds of formula (I) will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated.

Biological Assays

[0446] The compounds of formula (I) are useful in the treatment ofCXC-chemokine mediated conditions and diseases. This utility ismanifested in their ability to inhibit IL8 and GRO-α chemokine asdemonstrated by the following in vitro assays.

[0447] Receptor Binding Assays:

[0448] CXCR1 SPA Assay

[0449] For each well of a 96 well plate, a reaction mixture of 10 pghCXCR1-CHO overexpressing membranes (Biosignal) and 200 μg/well WGA-SPAbeads (Amersham) in 100 μl was prepared in CXCR1 assay buffer (25 mMHEPES, pH 7.8, 2 mM CaCl₂, 1 mM MgCl₂, 125 mM NaCl, 0.1% BSA) (Sigma). A0.4 nM stock of ligand, [125I]-IL-8 (NEN) was prepared in the CXCR1assay buffer. 20× stock solutions of test compounds were prepared inDMSO (Sigma). A 6× stock solution of IL-8 (R&D) was prepared in CXCR2assay buffer. The above solutions were added to a 96-well assay plate(PerkinElmer) as follows: 10 μl test compound or DMSO, 40 μl CXCR1 assaybuffer or IL-8 stock, 100 μl of reaction mixture, 50 μl of ligand stock(Final [Ligand]=0.1 nM). The assay plates were shaken for 5 minutes onplate shaker, then incubated for 8 hours before cpm/well were determinedin Microbeta Trilux counter (PerkinElmer). % Inhibition of Totalbinding-NSB (250 nM IL-8) was determined for IC₅₀ values.

[0450] Alternative CXCR1 SPA Assay

[0451] Protocol using CXCR1-expressing membranes from Biosignal Packard

[0452] For each 50 μl reaction, a working stock of 0.25 μg/μl hCXCR1-CHOover-expressing membranes with a specific activity of 0.05 pmol/mg(Biosignal Packard) and 25 μg/μl WGA-SPA beads (Perkin Elmer LifeSciences) was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 0.1mM CaCl₂, 1 mM MgCl₂, 100 mM NaCl) (Sigma). This mixture was incubatedon ice for 30 minutes and then centrifuged at 2500 rpm for 5 minutes.The beads and membranes were resuspended in CXCR1 assay buffer to thesame concentrations as in the original mixture. A 0.125 nM stock ofligand, [¹²⁵I]-IL-8 (Perkin Elmer Life Sciences), was prepared in theCXCR1 assay buffer. Test compounds were first serially diluted byhalf-logs in DMSO (Sigma) and then diluted 20-fold in CXCR1 assaybuffer. The above solutions were added to a Corning NBS (non-bindingsurface) 96-well assay plate as follows: 20 μl test compound or 5% DMSO(final [DMSO]=2%), 20 μl of membranes and SPA bead mixture (Final[membrane]=5 μg/reaction; Final [SPA bead]=500 μg/reaction), 10 μl ofligand stock (Final [¹²⁵I-IL-8]=0.025 nM). The assay plates wereincubated for 4 hours before cpm/well were determined in a MicrobetaTrilux counter (Perkin Elmer Life Sciences). IC₅₀ values were quantifiedusing nonlinear regression analysis in GraphPad Prism.

[0453] Alternative CXCR1 SPA Assay

[0454] Protocol Using CXCR1-Expressing Membranes from Euroscreen

[0455] For each 50 μl reaction, a working stock of 0.025 μg/[lhCXCR1-CHO overexpressing membranes with a specific activity of 3.47pmol/mg (Euroscreen) and 5 μg/μl WGA-SPA beads (Perkin Elmer LifeSciences) was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2.0mM CaCl₂, 1 mM MgCl₂, 125 mM NaCl) (Sigma). This mixture was incubatedon ice for 5 minutes. A 0.125 nM stock of ligand, [¹²⁵I]-IL-8 (PerkinElmer Life Sciences), was prepared in the CXCR1 assay buffer. Testcompounds were first serially diluted by half-logs in DMSO (Sigma) andthen diluted 13.3-fold in CXCR1 assay buffer. The above solutions wereadded to a Corning NBS (non-binding surface) 96-well assay plate asfollows: 20 μl test compound or 7.5% DMSO (final [DMSO]=3%), 20 μl ofmembranes and SPA bead mixture (Final [membrane]=0.5 μg/reaction; Final[SPA bead]=100 μg/reaction), 10 μl of ligand stock (Final[¹²⁵I-IL-8]=0.025 nM). The assay plates were incubated for 4 hoursbefore cpm/well were determined in a Microbeta Trilux counter (PerkinElmer Life Sciences). IC₅₀ values were quantified using nonlinearregression analysis in GraphPad Prism.

[0456] For the CXCR1 assay, compounds of formula (I) had an IC₅₀ of <20μM

[0457] CXCR2 SPA Assay

[0458] For each well of a 96 well plate, a reaction mixture of 4 μghCXCR2-CHO overexpressing membranes (Biosignal) and 200 μg/well WGA-SPAbeads (Amersham) in 100 μl was prepared in CXCR2 assay buffer (25 mMHEPES, pH 7.4, 2 mM CaCl₂, 1 mM MgCl₂). A 0.4 nM stock of ligand,[125I]-IL-8 (NEN), was prepared in the CXCR2 assay buffer. 20× stocksolutions of test compounds were prepared in DMSO (Sigma). A 6× stocksolution of GRO-α (R&D) was prepared in CXCR2 assay buffer. The abovesolutions were added to a 96-well assay plate (PerkinElmer or Corning)as follows: 10 μl test compound or DMSO, 40 μl CXCR2 assay buffer orGRO-α stock, 100 μl of reaction mixture, 50 μl of ligand stock (Final[Ligand]=0.1 nM). When 40× stock solutions of test compounds in DMSOwere prepared, then the above protocol was used except instead 5 μl testcompound or DMSO and 45 μl CXCR2 assay buffer were used. The assayplates were shaken for 5 minutes on a plate shaker, then incubated for2-8 hours before cpm/well were determined in Microbeta Trilux counter(PerkinElmer). % Inhibition of total binding minus non-specific binding(250 nM Gro-α or 50 μM antagonist) was determined and IC50 valuescalculated. Compounds of formula (I) had an IC₅₀ of <5 μM.

[0459] Alternative CXCR2 SPA Assay

[0460] Protocol Using the CXCR2 50 μl Assay

[0461] For each 50 μl reaction, a working stock of 0.031 μg/μlhCXCR2-CHO over-expressing membranes with a specific activity of 0.4pmol/mg (Biosignal Packard) and 2.5 μg/μl WGA-SPA beads (Perkin ElmerLife Sciences) was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4,2.0 mM CaCl₂, 1 mM MgCl₂) (Sigma). This mixture was incubated on ice for5 minutes. A 0.50 nM stock of ligand, [¹²⁵I]-IL-8 (Perkin Elmer LifeSciences), was prepared in the CXCR2 assay buffer. Test compounds werefirst serially diluted by half-logs in DMSO (Sigma) and then diluted13.3-fold in CXCR2 assay buffer. The above solutions were added to aCorning NBS (non-binding surface) 96-well assay plate as follows: 20 μltest compound or 7.5% DMSO (final [DMSO]=3%), 20 μl of membranes and SPAbead mixture (final [membrane]=0.625 μg/reaction; final [SPA bead]=50μg/reaction), 10 μl of ligand stock (final [¹²⁵I-IL-8]=0.10 nM). Theassay plates were incubated for 2 hours before cpm/well were determinedin a Microbeta Trilux counter (Perkin Elmer Life Sciences). IC₅₀ valueswere quantified using nonlinear regression analysis in GraphPad Prism.

[0462] Alternative CXCR2 SPA Assay

[0463] Protocol Using the CXCR2 200 μl Assay

[0464] For each 200 μl reaction, a working stock of 0.02 μg/μlhCXCR2-CHO overexpressing membranes with a specific activity of 0.6pmol/mg (Biosignal Packard) and 2 μg/μl WGA-SPA beads (Perkin Elmer LifeSciences) was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2.0mM CaCl₂, 1 mM MgCl₂) (Sigma). This mixture was incubated on ice for 5minutes. A 0.40 nM stock of ligand, [¹²⁵I]-IL-8 (Perkin Elmer LifeSciences), was prepared in the CXCR2 assay buffer. Test compounds werefirst serially diluted by half-logs in DMSO (Sigma) and then diluted20-fold in CXCR2 assay buffer. The above solutions were added to aCorning NBS (non-binding surface) 96-well assay plate as follows: 50 111test compound or 10% DMSO (final [DMSO]=2.5%), 100 μl of membranes andSPA bead mixture (final [membrane]=2 μg/reaction; final [SPA bead]=200μg/reaction), 50 μl of ligand stock (final [¹²⁵I-IL-8]=0.10 nM). Theassay plates were incubated for 2 hours before cpm/well were determinedin a Microbeta Trilux counter (Perkin Elmer Life Sciences). IC₅₀ valueswere quantified using nonlinear regression analysis in GraphPad Prism.

[0465] For the CXCR2 assay, compounds of formula (I) had a K_(t)<20 μM.

[0466] Carrageenan-Induced Rat Paw Edema Model

[0467] Carrageenan (0.05 ml of an 1% solution in saline) was injectedinto one hindpaw of male Sprague-Dawley rats. Paw volumes (ml) weremeasured by a water displacement plethysmometer prior to and 3 h afterthe injection of carrageenan. The increase in paw volume that occurredbetween the two timepoints was determined for each group. Rats receivedCompound A:

[0468] (see Example 405 of WO 02/083624) or standard drugs inmethylcellulose vehicle by the oral route, 1 hr before carrageenaninjection. The percentage by which the edematous response was inhibitedwas calculated by comparing the increase in paw edema of drug-treatedrats to that of vehicle-treated controls. To determine neutrophilaccumulation in the paws, rats were sacrificed at 3 hrs andmyeloperoxidase (MPO) activity was measured from inflammatory fluidexpressed from the hindpaw using a calorimetric assay (Bradley et al.,1982). PGE₂ production in the hindpaw was assessed by ELISA (R&DSystems, Minneapolis, Minn.).

[0469] Combination studies were performed with Compound A and thefollowing standard anti-inflammatory agents—the non-selectiveanti-inflammatory drug indomethacin, and the steroid betamethasone. Thecombination of suboptimal doses of compound A at 1 mg/kg (20%inhibition) and indomethacin at 0.5 mg/kg (0% inhibition) caused asignificant 41% reduction of paw edema, suggesting that this combinationresults in greater efficacy than either agent alone. This combinationdid not cause a further reduction in MPO activity in the hindpawcompared to compound A alone (Compound A=67% inhibition;indomethacin=−58% inhibition; combination=55% inhibition). Thecombination of suboptimal doses of Compound A at 1 mg/kg andbetamethasone at 0.05 mg/kg (32% inhibition) also demonstrated greaterefficacy in inhibiting edema (61% inhibition). An additive inhibition ofpaw PGE₂ levels was also observed (31% inhibition by eitherbetamethasone or Compound A alone, versus 78% inhibition with thecombination).

[0470] Streptococcal Cell Wall-Induced Mouse Knee Swelling Model

[0471] The method described by Lubberts et al, 1998 was used for thesestudies, with some modifications. Female 8-12 week old C57BL/6J animalswere fasted overnight and dosed orally with Compound A, indomethacin, ora combination of these agents suspended in methylcellulose one hourprior to a single intra-articular injection of 6 μl containing 25 μg ofbacterial SCW (4.32 mg/ml rhammose; Lee Laboratories, Grayson, Ga.) insaline into the right knee joint. The left knee joint received aninjection of 6 μl of saline at the same time. In other experiments, aneutralizing rat anti-mouse TNFα antibody or matched rat IgG isotypecontrol was administered intraperitoneally two hours prior to SCWinjection and Compound A or methylcellulose vehicle was orallyadministered one hour prior to SCW injection. Knee swelling measurementswere performed 2 hours after SCW injection using a dial-gauge caliper(Starret, Athol, Mass.) by measuring the difference in swelling betweenthe right and left knee joints. Patellar organ cultures for assessmentof synovial cytokine and chemokine and prostaglandin levels wereprepared at 2 hours after SCW injection and established as described(Lubberts et al, 1998), using ELISA kits obtained from R&D Systems(Minneapolis, Minn.). Statistical analysis was performed using theStudent's t-test, with p<0.05 considered to be indicative of statisticalsignificant differences between groups.

[0472] Combination therapy with Compound A (10 mg/kg=46% inhibition; 25mg/kg=70% inhibition) and indomethacin (2 mg/kg=42% inhibition) resultedin significantly greater reduction of knee swelling compared to eitheragent alone in all instances. Thus, the combination of Compound A at 10mg/kg with indomethacin resulted in a 74% inhibition of the response,while Compound A at 25 mg/kg in combination with indomethacin led to a93% inhibition of the swelling response. Compound A administered alonesignificantly inhibited IL-1β production by ex vivo patellar organculture (49% inhibition at 10 mg/kg; 64% inhibition at 25 mg/kg) whileindomethacin treatment resulted in a 11% inhibition. Combinationtreatment resulted in a 71% (10 mg/kg Compound A+indomethacin) and 57%inhibition (25 mg/kg Compound A+indomethacin) of IL-1β production,consistent with the concept that the effect on IL-1β was attributable tothe pharmacological action of Compound A. In comparison, the effect ofcombination therapy on PGE₂ levels (86% and 85% inhibition,respectively) in patellar organ culture was accounted for by theactivity of indomethacin alone (89% inhibition) while Compound A alonehad mild activity (34-40% inhibition at 10-25 mg/kg).

REFERENCES

[0473] Bradley, P. P., D. A. Priebat, R. D. Christensen and G.Rothstein. 1982. Measurement of cutaneous inflammation: Estimation ofneutrophil content with an enzyme marker. J. Invest. Dermatol.78:206-209.

[0474] Lubberts, E., L. A. B. Joosten, M. M. A. Helsen and W. B. van denBerg. 1998. Regulatory role of interleukin 10 in joint inflammation andcartilage destruction in murine streptococcal cell wall (SCW) arthritis.More therapeutic benefit with IL-4/IL-10 combination therapy than withIL-10 treatment alone. Cytokine 10:361-369.

[0475] Compounds of formula (I) may be produced by processes known tothose skilled in the art, in the following reaction schemes, and in thepreparations and examples below. Specific procedures for the preparationof many of the compounds of formula (I) may be found in in WO 02/076926published Oct. 3, 2002, and WO 02/083624 published Oct. 24, 2002.

[0476] A general procedure for the preparation of compounds of formula(I) is as follows:

[0477] Scheme 1

[0478] An amine is condensed (Step A) with a nitrosalicylic acid understandard coupling conditions and the resulting nitrobenzamide is reduced(Step B) under hydrogen atmosphere in the presence of a suitablecatalyst. The remaining partner required for the synthesis of the finaltarget is prepared by condensing an aryl amine with the commerciallyavailable diethylsquarate to give the aminoethoxysquarate product.Subsequent condensation of this intermediate with the aminobenzamideprepared earlier provides the desired chemokine antagonist (Scheme 1).

[0479] Scheme 2

[0480] Alternatively, the aminobenzamide of Scheme 1 is first condensedwith commercially available diethylsquarate to give an alternatemonoethoxy intermediate. Condensation of this intermediate with an aminegives the desired chemokine antagonist.

[0481] Scheme 3

[0482] Benztriazole compounds of Formula (I) are prepared by stirringnitrophenylenediamines with sodium nitrite in acetic acid at 60° C. toafford the nitrobenzotriazole intermediate (Scheme 3). Reduction of thenitro group in the presence of palladium catalyst and hydrogenatmosphere provides the amine compound. Subsequent condensation of thisintermediate with the aminooethoxysquarate prepared earlier (Scheme 1)provides the desired chemokine antagonist.

[0483] Scheme 4

[0484] Condensation of nitrophenylenediamines with anhydrides oractivated acids at reflux (Scheme 4) affords benzimidazole intermediateswhich after reduction with hydrogen gas and palladium catalyst andcondensation with the aminoethoxysquarate previously prepared (Scheme 1)affords benzimidazole chemokine antagonists.

[0485] Scheme 5

[0486] Indazole structures of Formula (I) can be prepared according toScheme 5 by reduction of nitroindazole A (J. Am. Chem Soc. 1943, 65,1804-1805) to give aminoindazole B and subsequent condensation with theaminoethoxysquarate prepared earlier (Scheme 1).

[0487] Scheme 6

[0488] Indole structures of Formula (I) can be prepared according toScheme 6 by reduction of nitroindole A (J. Med. Chem. 1995, 38,1942-1954) to give aminoindole B and subsequent condensation with theaminoethoxysquarate prepared earlier (Scheme 1).

[0489] The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures may be apparent to those skilled in the art.

PREPARATIVE EXAMPLES 13.17A-13.17B

[0490] Following the procedure set forth in Preparative Example 13.13 inWO 02/083624, but using the prepared or commercially availablealdehydes, the optically pure amine products in the Table below wereobtained. Prep Ex. Aldehyde Amine Product Yield (%) 13.17A

38 13.17B

31

PREPARATIVE EXAMPLE 13.29

[0491]

[0492] Step A

[0493] To a solution of 3-methoxythiophene (3 g) in dichloromethane (175mL) at −78° C. was added chlorosulfonic acid (8.5 mL) dropwise. Themixture was stirred for 15 min at −78° C. and 1.5 h at room temp.Afterwards, the mixture was poured carefully into crushed ice, andextracted with dichloromethane. The extracts were washed with brine,dried over magnesium sulfate, filtered through a 1-in silica gel pad.

[0494] The filtrate was concentrated in vacuo to give the desiredcompound (4.2 g).

[0495] Step B

[0496] The product from Step A above (4.5 g) was dissolved indichloromethane (140 mL) and added with triethylamine (8.8 mL) followedby diethyl amine in THF (2M, 21 mL). The resulting mixture was stirredat room temperature overnight. The mixture was washed with brine andsaturated bicarbonate (aq) and brine again, dried over sodium sulfate,filtered through a 1-in silica gel pad. The filtrate was concentrated invacuo to give the desired compound (4.4 g).

[0497] Step C

[0498] The product from Step B above (4.3 g) was dissolved indichloromethane (125 mL) and cooled in a −78° C. bath. A solution ofboron tribromide (1.0 M in dichloromethane, 24.3 mL) was added. Themixture was stirred for 4 h while the temperature was increased slowlyfrom −78° C. to 10° C. H₂O was added, the two layers were separated, andthe aqueous layer was extracted with dichloro-methane.

[0499] The combined organic layer and extracts were washed with brine,dried over magnesium sulfate, filtered, and concentrated in vacuo togive 3.96 g of the desired hydroxy-compound.

[0500] Step D

[0501] The product from step C above (3.96 g) was dissolved in 125 mL ofdichloromethane, and added with potassium carbonate (6.6 g) followed bybromine (2 mL). The mixture was stirred for 5 h at room temperature,quenched with 100 mL of H₂O. The aqueous mixture was addjusted to pH ˜5using a 0.5N hydrogen chloride aqueous solution, and extracted withdichloromethane. The extracts were washed with a 10% Na₂S₂O₃ aqueoussolution and brine, dried over sodium sulfate, and filtered through acelite pad. The filtrate was concentrated in vacuo to afford 4.2 g ofthe desired bromo-compound.

[0502] Step E

[0503] The product from Step D (4.2 g) was dissolved in 100 mL ofacetone and added with potassium carbonate (10 g) followed byiodomethane (9 mL). The mixture was heated to reflux and continued for3.5 h. After cooled to room temperature, the mixture was filteredthrough a Celite pad. The filtrate was concentrated in vacuo to a darkbrown residue, which was purified by flash column chromatography elutingwith dichloromethane-hexanes (1:1, v/v) to give 2.7 g of the desiredproduct.

[0504] Step F

[0505] The product from step E (2.7 g) was converted to the desiredimine compound (3 g), following the similar procedure to that ofPreparative Example 13.19 step D.

[0506] Step G

[0507] The imine product from step F (3 g) was dissolved in 80 mL ofdichloromethane and cooled in a −78° C. bath. A solution of borontribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. Themixture was stirred for 4.25 h from −78° C. to 5° C. H₂O (50 mL) wasadded, and the layers were separated. The aqueous layer was extractedwith dichloromethane. The organic layer and extracts were combined,washed with brine, and concentrated to an oily residue. The residue wasdissolved in 80 mL of methanol, stirred with sodium acetate (1.5 g) andhydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. Themixture was poured into an aqueous mixture of sodium hydroxide (1.0 Maq, 50 mL) and ether (100 mL). The two layers were separated. Theaqueous layer was washed with ether three times. The combined etherwashings were re-extracted with H₂O once. The aqueous layers werecombined, washed once with dichloromethane, adjusted to pH ˜6 using 3.0M and 0.5 M hydrogen chloride aqueous solutions, and extracted withdichloromethane. The organic extracts were combined, washed with brine,dried over sodium sulfate, and concentrated in vacuo to give 1.2 g ofdesired amine compound.

PREPARATIVE EXAMPLES 13.30-13.32-A

[0508] Following the procedures set forth in Example 13.29, but usingcommercially available amines, hydroxy-amino-thiophene products in theTable below were obtained. Yield Prep Ex. Amine Product MH⁺ 13.30(Bn)₂NH

10% 375.1 13.31 Me(Bn)NH

14% 299.0 13.32 Et(Bn)NH

22% 13.32A (Et)₂NH

25%

PREPARATIVE EXAMPLE 13.33

[0509]

[0510] Step A

[0511] 2-Chlorosulfonyl-3-methoxy-thiophene (4.0 g, 18.8 mmol), theproduct from Step A of Preparative Example 13.29 was converted to3-methoxy-2-ethylbenzylsulfonyl-thiophene (5.5 g, 94%, MH⁺=312.1) byusing ethylbenzyl-amine, following the procedure set forth inPreparative Example 13.29, Step B.

[0512] Step B

[0513] 10 The product from Step A above (5.5 g, 17.70 mmol) wasdemethylated following the procedure set forth in Preparative Example13.29, Step C. The alcohol product was obtained in 4.55 g (87%,MH⁺=298.0).

[0514] Step C

[0515] The product from Step B above (4.55 g, 15.30 mmol) was brominatedusing the procedure set forth in Preparative Example 13.29, Step D. Thecorresponding bromide was obtained in 4.85 g (84%).

[0516] Step D

[0517] The bromo-alcohol from Step C above (4.84 g, 12.86 mmol) wasmethylated using the procedure set forth in Preparative Example 13.29,Step E. The product was obtained in 4.82 g (96%).

[0518] Step E

[0519] The product from Step D above (4.82 g, 12.36 mmol) was stirredwith concentrated sulfuric acid (5 mL) at room temperature ro 3 h. Icewater (30 mL) was added to the mixture followed by CH₂Cl₂ (50 mL). Theaqueous mixture was adjusted to pH ˜6 using a 1.0 M NaOH aqueoussolution. The layers were separated. The aqueous layer was extractedwith CH₂Cl₂ (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, and concentrated to a dark brown oil, whichwas purified by flash column chromatography, eluting with CH₂Cl₂-hexanes(1:1, v/v). Removal of solvents afforded 3.03 g (82%) of thedebenzylated product (M⁺=300.0, M+2=302.0).

[0520] Step F

[0521] The product from Step E (1.34 g, 4.45 mmol) was methylated usingthe procedure set forth in Preparative Example 13.29, Step E. Thedesired product was obtained in 1.36 g (97%, M⁺=314.1, M+2=316.0).

[0522] Step G

[0523] The product from Step F (1.36 g, 4.33 mmol) was converted toimine product (1.06 g, 55%, MH⁺=415.1) using the procedure set forth inPreparative Example 13.29, Step F.

[0524] Step H

[0525] The imine product from Step G (1.06 g, 2.56 mmol) was convertedto the desired hydroxy-amino thiophene compound (0.26 g, 43%) using theprocedure set forth in Preparative Example 13.29, Step G.

[0526] PREPARATIVE EXAMPLE 13.34

[0527] Step A

[0528] 2-Chlorosulfonyl-3-methoxy-thiophene (3.8 g, 17.87 mmol), theproduct from step A of Preparative Example 13. 29, was dissolved in 100mL of CH₂Cl₂ and 20 mL of pyridine. 3-Amino-5-methyl-isoxazole (3.5 g,35.68 mmol) was added. The mixture was stirred for 20 h at roomtemperature, diluted with 100 mL of CH₂Cl₂, and washed with a 0.5 N HClaqueous solution (50 mL×2), H₂O (50 mL), and brine (50 mL). The organicsolution was dried with Na₂SO₄, and conentrated in vacuo to a brown oil.This oil was dissolved in 100 mL of CH₂Cl₂, washed again with a 0.5 MHCl aqueous solution (30 mL×3) and brine. After dried over Na₂SO₄, theorganic solution was concentrated in vacuo to a yellow solid, 4.48 g(91%, MH⁺=275.0) of the desired product.

[0529] Step B

[0530] The product from Step A above (4.48 g, 16.33 mmol) was dissolvedin acetone (100 mL), added with potassium carbonate (5.63 g, 40.80 mmol)and iodomethane (10.1 mL, 163.84 mmol). The mixture was stirred at roomtemperature for 1.5 h, diluted with 100 mL of hexanes and 50 mL ofCH₂Cl₂, and filtered through a 1-in silica gel pad, rinsing with CH₂Cl₂.The filtrate was concentrated under reduced pressure to give 4.23 g(90%, MH⁺=289.0) of the desired product as a light yellow solid.

[0531] Step C

[0532] To a stirred suspension of sodium hydride (130 mg, 95%, 5.4 mmol)in 8 mL of N,N′-dimethylforamide at room temperature was addedethanethio](0.45 mL, 6.0 mmol) dropwise. After 5 min, the mixture becamea clear solution, and was added to a stirred solution of the productobtained from Step B above (0.45 g, 1.56 mmol) in 2 mL ofN,N′-dimethylforamide in a round bottom flask. The flask was sealed witha ground glass stopper, and the mixture was heated at 90-95° C. for 4 h.After cooled to room temperature, the mixture was poured into 20 mL of a1.0 M NaOH aqueous solution, further rinsed with 20 mL of H₂O. Theaqueous mixture was washed with diethyl ether (30 mL×2), adjusted to PH˜5 using a 0.5 M HCl aqueous solution, and extracted with CH₂Cl₂ (50 mLx4). The combined extracts were washed with brine, dried (Na₂SO₄), andconcentrated to a dark yellow solution. This was dissolved in 50 mL ofethyl acetate, washed with H₂O (30 mL x2) and brine (30 mL), dried overNa₂SO₄. Evaporation of solvent gave 0.422 g of the alcohol product (99%,MH⁺=275.0).

[0533] Step D

[0534] The alcohol obtained from Step C above (0.467 g, 1.70 mmol) wasbrominated using the procedure set forth in Preparative Example 13.29,Step D, to afford the corresponding bromide in 0.607 g (100%).

[0535] Step E

[0536] The bromide obtained from Step D above (0.607 g, 1.72 mmol) wasmethylated using the procedure set forth in Preparative Example 13.29,Step E, to give the desired product in 0.408 g (65%, M⁺=367, M+2=369.1).

[0537] Step F

[0538] The product (0.405 g, 1.103 mmol) from Step E above was convertedto the imine compound (0.29 g, 56%) using the procedure set forth inPreparative Example 13.29, Step F.

[0539] Step G

[0540] The imine product obtained from Step F above (0.29 g, 0.61 mmol)was demethylated using the procedure set forth in Step C above to givethe corresponding alcohol as a dark yellow oil, which was dissolved in 5mL methanol and added with sodium acetate (0.12 g, 1.46 mmol) andhydroxyamine hydrochloride (0.075 g, 1.08 mmol). The resulting mixturewas stirred at room temperature for 3 h, and poured into 10 mL of 1.0 MNaOH aqueous solution. 30 mL of H₂O was used as rinsing and combined tothe aqueous layer. The aqueous mixture was washed with diethyl ether (40mL×3), adjusted to pH ˜6 using a 1.0 M HCl aqueous solution, andextracted with ethyl acetate (40 mL×3). The organic extracts were washedwith H₂O (20 mL×2), brine (20 mL), dried over Na₂SO₄, and concentratedin vacuo to give 0.112 g of the desired hydroxy-amino thiophenesulfonamide (64%, MH⁺=290).

PREPARATIVE EXAMPLE 13.35

[0541]

[0542] Step A

[0543] To a solution of 2-methyl furan (1.72 g) in ether was added BuLi(8.38 mL) at −78° C. and stirred at room temperature for half an hour.The reaction mixture again cooled to −78° C. and quenched withcyclopropyl amide 1 and stirred for two hours at −78° C. and slowlywarmed to room temperature. The reaction mixture stirred for three hoursat room temperature and quenched with the addition of saturated ammoniumchloride solution. The mixture was taken to a separatory funnel, washedwith water, brine and dried over anhydrous sodium sulfate. Filtrationand removal of solvent afforded the crude ketone, which was purified byusing column chromatography to afford the ketone 3.0 g (87%) as a paleyellow oil.

[0544] Step B

[0545] To a solution of ketone (1.0 g) in THF (5.0 mL) at 0° C. wasadded R-methyl oxazoborolidine (1.2 mL, 1 M in toluene) dropwisefollowed by addition of a solution of borane complexed with dimethylsulfide (1.85 mL, 2M in THF). The reaction mixture was stirred for 30minutes at 0° C. and than at room temperature for one hour. The reactionmixture was cooled to 0° C. and MeOH was added carefully. The mixturewas stirred for 20 minutes and was concentrated under reduced pressure.The residue was extracted with ether, washed with water, 1 M HCl (10mL), saturated sodium bicarbonate (10.0 mL) water and brine. The organiclayer was dried over anhydrous sodium sulfate, filtered and removal ofsolvent afforded the crude alcohol which was purified by silica gelchromatography to afford the pure alcohol 0.91 g (91%) as yellow oil.

PREPARATIVE EXAMPLE 13.36

[0546]

[0547] Step A

[0548] An equimolar mixture of 2-methylfuran (1.0 g) and anhydride (2.6g) was mixed with SnCl₄ (0.05 mL) and heated at 100° C. for 3 hours.After cooling the reaction mixture, water (10 mL) was added, followed bysaturated sodium carbonate solution until it becomes alkaline. Thereaction mixture was extracted with ether several times and the combinedether layer was washed with water, brine and dried over anhydrous sodiumsulfate. Filtration and removal of solvent afforded the crude ketone,which was purified by using silica gel chromatography to afford theketone 0.9 g (43%) as a yellow oil.

[0549] Step B

[0550] The step B alcohol was obtained following a similar procedure setforth in the preparative example 13.35 Step B.

PREPARATIVE EXAMPLE 13.37

[0551]

[0552] Step A

[0553] To a solution of 5-methyl furan-2-aldehyde (1.0 g) and3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added indiumpowder (1.66 g) and lithium iodide (50.0 mg). The reaction mixture wasstirred over night, diluted with water and extracted with ether. Theether layer was washed with water, brine and purified by silicagelchromatography to afford the pure alcohol 2.8 g (92%).

PREPARATIVE EXAMPLES 13.38-13.45

[0554] Following a similar procedure set forth in Preparative Examples13.25 and 13.35, and using the indicated Furan and Electrophile, thefollowing Alcohols in the Table below were prepared. Prep. Ex FuranElectrophile Alcohol Yield 13.38

86% 13.39

69% 13.40

84% 13.41

82% 13.42

60% 13.43

65% 13.44

82% 13.45

89%

PREPARATIVE EXAMPLES 13.50-13.61

[0555] Following a similar procedure set forth in WO 02/083624,Preparative Example 13.25, and using the indicated Alcohol, the Aminesin the Table below were prepared. PREP. EX. ALCOHOL AMINE YIELD 13.5013.45

28% 13.51 13.38

58% 13.52 13.36

69% 13.53 13.35

81% 13.54 13.37

82% 13.55 13.39

45% 13.56 13.41

57% 13.57 13.40

58% 13.58 13.44

54% 13.59 13.42

53% 13.60 13.43

50% 13.61 13.37

82%

PREPARATIVE EXAMPLE 13.70

[0556]

[0557] Step A

[0558] The imine was prepared following the procedure set forth in WO02/083624 Preparative Example 13.19 from the known bromoester (1.0 g) asa yellow solid, Step A to yield 1.1 g (79%).

[0559] Step B

[0560] The Step A product (0.6 g) was reacted following the procedureset forth in the preparative example 13.19 to give the amine product0.19 g (64%).

[0561] Step C

[0562] The Step B product (1.0 g) was reacted following the procedureset forth in WO 02/083624 Preparative Example 13.19 to give the acid asyellow solid 0.9 g (94%).

[0563] Step D

[0564] The Step C product (0.35 g) was reacted following the procedureset forth in WO 02/083624 Preparative Example 13.19 to give the aminoacid as yellow solid 0.167 g (93%).

PREPARATIVE EXAMPLE 13.71

[0565]

[0566] Following a similar procedure set forth in Preparative Example13.33 Step E, but using the product from WO 02/083624 PreparativeExample 13.32, the title compound was obtained (121 mg, 69% yield,MH+=223.0).

PREPARATIVE EXAMPLE 23.15A-23.15E

[0567] Following the procedures set forth in WO 02/083624 PreparativeExample 19.2 but using the amines from the Preparative Example indicatedin the Table below, the corresponding cyclobutenedione intermediateswere prepared. Amine from Prep Prep 1. Yield Ex. Ex. Product 2. MH⁺23.15F 13.32A

1. 68% 2. 375.1

PREPARATIVE EXAMPLE 24

[0568] Following the procedures set forth in WO 02/083624 PreparativeExample 13.23 (but instead using 5-bromo-6-methoxybenzoic acid in StepA) and in WO 02/083624 Preparative Example 23.14, the correspondingcyclobutenedione intermediate could be prepared.

PREPARATIVE EXAMPLE 25

[0569] Following the procedures set forth in Preparative Example 13.24(but instead using 2-aminopyridine) and in WO 02/083624 PreparativeExample 23.14, the corresponding cyclobutenedione intermediate could beprepared.

PREPARATIVE EXAMPLE 26

[0570] Following the procedures set forth in WO 02/083624 PreparativeExample 23.14 (but instead the title compound from WO 02/083624Preparative Example 135), the corresponding cyclobutenedioneintermediate could be prepared.

PREPARATIVE EXAMPLE 34.15-34.16

[0571] Following the procedures set forth in Preparative Example 34.8 inWO 02/083624 but using the nitroalkanes indicated in the table below,the aldehydes were prepared. YIELD PREP. Ex. NITROALKANE ALDEHYDE (%)34.15

17 34.16

21

PREPARATIVE EXAMPLE 34.17

[0572]

[0573] Step A

[0574] To a stirred suspension of 5-bromo-2-furoic acid (15.0 g, 78.54mmol) in 225 mL of CH₂Cl₂ at room temperature was added oxalyl chloridefollowed by a catalytic amount of N,N′-dimethylforamide. After 1 h,ethanol (20 mL) was added followed by triethylamine (22 mL). Reactionwas continued for 15 h. The mixture was concentrated under reducedpressure to a residue, which was extracted with excess volume ofhexanes, and hexanes-CH₂Cl₂ (3:1, v/v). The extracts were filtered, thefiltrated was concentrated to a yellow oil, dried on high vacuum,yielding 17.2 g (93%) of the desired ester.

[0575] Step B

[0576] The ester product obtained from Step A above (17.2 g, 73.18 mmol)was converted to 2-ethyl-4-tertbutyl-5-bromo-furoate (7.9 g, 37%) usingthe literature procedure: J. Am. Chem.Soc., 1939, 61, 473-478 (thedisclosure of which is incorporated herein by reference thereto).

[0577] Step C

[0578] The ester product obtained from Step B above (7.9 g, 27.13 mol)was reduced to the alcohol (6.32 g) using the procedure set forth in WO02/083624 Preparative Example 34.8, Step C.

[0579] Step D

[0580] The product obtained from Step C above (6.32 g) was dissolved in140 mL of THF and cooled in a −78° C. bath. A 2.5 M solution ofn-butyllithium in hexanes (22 mL, 55.0 mmol) was added dropwise alongthe side wall of the flask. After 15 min, H₂O (˜70 mL) was added.Cooling bath was removed, the mixture was stirred for an additional 1 h.Brine (50 mL) and CH₂Cl₂ (300 mL) were added, the two layers wereseparated, the aqueous layer was extracted with CH₂Cl₂ (100 mL), and thecombined organic layers ere dried by Na₂SO₄. Evaporation of solventsafforded 5.33 g (crude) of the debrominated product as a reddish brownoil.

[0581] Step E

[0582] The alcohol product obtained from Step D above (5.33 g) wasoxidized to the corresponding aldehyde (3.06 g, 74% over three steps)using the procedure set forth in WO 02/083624 Preparative Example 34.8,Step D.

[0583] PREPARATIVE EXAMPLE 34.18

[0584] Step A

[0585] To a stirred solution of cyclopropyl bromide (4.0 mL, 50 mmol) in120 mL of ether at −78° C. was added dropwise a 1.7M solution oft-butyllithium in pentane (44.5 mL, 75.7 mmol). After 10 min, coolingbath was removed, stirring was continued for 1.5 h. The mixture wascooled again in a −78° C. bath, and 3-furaldehyde (3.5 mL, 41.9 mmol)was added. Reaction was continued for 1 h, and quenched with a saturatedNH4Cl aqueous solution. The aqueous mixture was extracted with CH₂Cl₂(100 mL×3). The organic extracts were washed with brine, dried byNa₂SO₄, filtered, and concentrated in vacuo to give 5.3 g (91%) of thealcohol product as a yellow oil.

[0586] Step B

[0587] Chloro trimethylsilane (27.2 mL, 214.2 mmol) was added dropwiseto a vigorously stirred suspension of sodium iodide (32 g, 213.5 mmol)in 100 mL of acetonitrile. After 5 min, a solution of the alcoholobtained from Step A above (4.93 g, 35.68 mmol) in 100 mL ofacetonitrile was added dropwise. Stirring was continued for 5 min. H₂O(100 mL) was added, the layers were separated, and the aqueous layer wasextracted with ether (100 mL×2). The organic layers were combined,washed with a 10% Na₂S₂O₃ aqueous solution and brine, and dried overNa₂SO₄. Evaporation of solvents gave a dark brown oil, which wasfiltered through a 5-in silica gel column, eluting with CH₂Cl₂-hexanes(1:3.5, v/v). Removal of solvents afforded 4.22 g (47%) of the iodoproduct as a light yellow oil.

[0588] Step C

[0589] The iodo-product obtained from Step B above (2.2 g, 8.8 mmol) wasdissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 Msolution of t-butyllithium in pentane (10.4 mL, 17.7 mmol) was addeddropwise. After 20 min, cooling bath was removed. Reaction was continuedfor 2.5 h, and quenched with H₂O (20 mL). The aqueous mixture wasstirred overnight and separated. The aqueous layer was extracted withether (30 mL). The combined organic layers were washed with brine, driedby Na₂SO₄, and filtered through a Celite pad. Removal of solvent gave1.10 g (100%) of 3-butylfuran as a reddish-yellow oil.

[0590] Step D

[0591] 3-Butylfuran (1.1 g, 8.8 mmol), obtained from Step C above, wasdissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 Msolution of t-butyllithium in pentane (6.0 mL, 10.2 mmol) was addeddropwise along the side wall of the flask. The mixture was stirred for 3h from −78° C. to 0° C., and continued for 1 h at room temperature. Asolution of N,N′-dimethylforamide (1.1 mL, 14.23 mmol) was added.Reaction was continued overnight, and quenched with a saturated NH₄Claqueous solution. The two layers were separated, the aqueous layer wasextracted with CH₂Cl₂ (30 mL×2). The combined organic layers were washedwith brine, dried with Na₂SO₄, and concentrated to an oil, which waspurified by preparative TLC (CH₂Cl₂— hexanes=1:1.5, v/v) to give 0.48 g(36%) of the aldehyde (contaminated by some 3-butyl-2-furaldehyde).

PREPARATIVE EXAMPLE 34.19

[0592]

[0593] Step A

[0594] 3-Ethylfuran was prepared from 3-hydroxymethylfuran according toliterature procedure: J. Org. Chem., 1983, 48, 1106-1107 (the disclosureof which is incorporated herein by reference thereto).

[0595] Step B

[0596] 3-Ethylfuran obtained from Step A above was converted to4-ethyl-2-furaldehyde using the procedure set forth in WO 02/083624Preparative Example 34.18, Step D.

PREPARATIVE EXAMPLES 65-75.10J

[0597] Following the procedure set forth in WO 02/083624 PreparativeExample 64 but using the aldehydes, amino alcohols, and organolithiumreagents in the Table below (prepared according to the PreparativeExamples indicated from WO 02/083624), the optically pure amine productsin the Table below were obtained. Prep Amino Organo 1. Yield (%) Ex.Aldehyde Alcohol lithium Product 2. MH⁺ 75.10A

1. 61 2. 135 [M − NH₂]⁺ 75.10B

EtLi

1. 24 2. 154 75.10C

EtLi

1. 32 2. 165 [M − NH₂]⁺ 75.10D

MeLi

1. 47 2. 137 [M − NH₂]⁺ 75.10E

iPrLi

1. 30 2. 165 [M − NH₂]⁺ 75.10F

1. 67 2. 163.0 [M − NH₂]⁺ 75.10G

EtLi

1. 24 2. 165 [M − NH₂]⁺ 75.10H

EtLi

1. 70 2. 194 75.10J

EtLi

1. 54 2. 208

PREPARATIVE EXAMPLES 75.11-75.59

[0598] Following the procedure set forth in WO 02/083624 PreparativeExample 64 but using the prepared or commercially available aldehydes,amino alcohols, and organolithium reagents in the Table below andcarrying the amine on crude, the optically pure amine products in theTable below were obtained. Prep Amino Organo Yield Ex. Aldehyde Alcohollithium Product (%) 75.60

t-BuLi

60

PREPARATIVE EXAMPLE 500.7

[0599]

[0600] Step A

[0601] If one were to use a similar procedure to that used in WO02/083624 Preparative Example 13.3 Step B, except using the hydroxy acidfrom Bioorg. Med. Chem. Lett. 6(9), 1996,1043 (the disclosure of whichis incorporated herein by reference thereto), one would obtain thedesired methoxy compound.

[0602] Step B

[0603] If one were to use a similar procedure to that used in WO02/083624 Preparative Example 13.19 Step B, except using the productfrom Step A above, one would obtain the desired compound.

[0604] Step C

[0605] If one were to use a similar procedure to that used in Synth.Commun. 1980, 10, p. 107 (the disclosure of which is incorporated hereinby reference thereto), except using the product from Step B above andt-butanol, one would obtain the desired compound.

[0606] Step D

[0607] If one were to use a similar procedure to that used in Synthesis,1986,1031 (the disclosure of which is incorporated herein by referencethereto), except using the product from Step C above, one would obtainthe desired sulfonamide compound.

[0608] Step E

[0609] If one were to use a similar procedure to that used in WO02/083624 Preparative Example 13.19 Step E, except using the productfrom Step D above, one would obtain the desired compound.

PREPARATIVE EXAMPLE 500.8

[0610]

[0611] Step A

[0612] If one were to treat the product from Step C of WO 02/083624Example 1125 with BuLi (2.2 eq.) in THF followed by quenching of thereaction mixture with N,N,-dimethylsulfamoyl chloride (1.1 eq.) then onewould obtain the title compound.

[0613] Step B

[0614] If one were to use the product of Step A above and follow Step Eof Preparative Example 500.7, then one would obtain the title compound.

PREPARATIVE EXAMPLE 500.9

[0615]

[0616] Step A

[0617] To a solution of 3-methoxythiophene (3 g) in dichloromethane (175mL) at −78° C. was added chlorosulfonic acid (8.5 mL) dropwise. Themixture was stirred for 15 min at −78° C. and 1.5 h at room temp.Afterwards, the mixture was poured carefully into crushed ice, andextracted with dichloromethane. The extracts were washed with brine,dried over magnesium sulfate, filtered through a 1-in silica gel pad.The filtrate was concentrated in vacuo to give the desired compound (4.2g).

[0618] Step B

[0619] The product from Step A above (4.5 g) was dissolved indichloromethane (140 mL) and added with triethylamine (8.8 mL) followedby diethyl amine in THF (2M, 21 mL). The resulting mixture was stirredat room temperature overnight. The mixture was washed with brine andsaturated bicarbonate (aq) and brine again, dried over sodium sulfate,filtered through a 1-in silica gel pad. The filtrate was concentrated invacuo to give the desired compound (4.4 g).

[0620] Step C

[0621] The product from Step B above (4.3 g) was dissolved indichloromethane (125 mL) and cooled in a −78° C. bath. A solution ofboron tribromide (1.0 M in dichloromethane, 24.3 mL) was added. Themixture was stirred for 4 h while the temperature was increased slowlyfrom −78° C. to 10° C. H₂O was added, the two layers were separated, andthe aqueous layer was extracted with dichloro-methane. The combinedorganic layer and extracts were wahed with brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo to give 3.96 g of thedesired hydroxy-compound.

[0622] Step D

[0623] The product from step C above (3.96 g) was dissolved in 125 mL ofdichloromethane, and added with potassium carbonate (6.6 g) followed bybromine (2 mL). The mixture was stirred for 5 h at room temperature,quenched with 100 mL of H₂O. The aqueous mixture was addjusted to pH ˜5using a 0.5N hydrogen chloride aqueous solution, and extracted withdichloromethane. The extracts were washed with brine, dried over sodiumsulfate, and filtered through a celite pad. The filtrate wasconcentrated in vacuo to afford 4.2 g of the desired bromo-compound.

[0624] Step E

[0625] The product from Step D (4.2 g) was dissolved in 100 mL ofacetone and added with potassium carbonate (10 g) followed byiodomethane (9 mL). The mixture was heated to reflux and continued for3.5 h. After cooled to room temperature, the mixture was filteredthrough a Celite pad. The filtrate was concentrated in vacuo to a darkbrown residue, which was purified by flash column chromatography elutingwith dichloromethane-hexanes (1:1, v/v) to give 2.7 g of the desiredproduct.

[0626] Step F

[0627] The product from step E (2.7 g) was converted to the desiredimine compound (3 g), following the similar procedure to that of WO02/083624 Preparative Example 513.19step D.

[0628] Step G

[0629] The imine product from step F (3 g) was dissolved in 80 mL ofdichloromethane and cooled in a −78° C. bath. A solution of borontribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. Themixture was stirred for 4.25 h from −78° C. to 5° C. H₂O (50 mL) wasadded, and the layers were separated. The aqueous layer was extractedwith dichloromethane. The organic layer and extracts were combined,washed with brine, and concentrated to an oily residue. The residue wasdissolved in 80 mL of methanol, stirred with sodium acetate (1.5 g) andhydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. Themixture was poured into an aqueous mixture of sodium hydroxide (1.0 Maq, 50 mL) and ether (100 mL). The two layers were separated. Theaqueous layer was washed with ether three times. The combined etherwashings were re-extracted with H₂O once. The aqueous layers werecombined, washed once with dichloromethane, adjusted to pH ˜6 using 3.0M and 0.5 M hydrogen chloride aqueous solutions, and extracted withdichloromethane. The organic extracts were combined, washed with brine,dried over sodium sulfate, and concentrated in vacuo to give 1.2 g ofdesired amine compound.

PREPARATIVE EXAMPLE 600

[0630]

[0631] Step A

[0632] Following the procedure set forth in WO 02/083624 PreparativeExample 13.19 Step D, the imine was prepared from the known bromoester(1.0 g) to yield 1.1 g (79%) as a yellow solid.

[0633] Step B

[0634] The product of Step A (0.6 g) was reacted following the procedureset forth in WO 02/083624 Preparative Example 13.19 Step E to give theamine product 0.19 g (64%).

[0635] Step C

[0636] The product of Step B (1.0 g) was reacted following the procedureset forth in WO 02/083624 Preparative Example 13.19 Step B to give theacid as yellow solid 0.9 g (94%).

[0637] Step D

[0638] The product of Step C (0.35 g) was reacted following theprocedure set forth in WO 02/083624 Preparative Example 13.19 Step E togive the amino acid as yellow solid 0.167 g (93%).

PREPARATIVE EXAMPLE 601

[0639]

[0640] Step A

[0641] To a solution of 2-methyl furan (1.72 g) in ether was added BuLi(8.38 mL) at −78° C. and stirred at room temperature for half an hour.The reaction mixture again cooled to −78° C. and quenched withcyclopropyl amide 1 and stirred for two hours at −78° C. and slowlywarmed to room temperature. The reaction mixture stirred for three hoursat room temperature and quenched with the addition of saturated ammoniumchloride solution. The mixture was taken to a separatory funnel, washedwith water, brine and dried over anhydrous sodium sulfate. Filtrationand removal of solvent afforded the crude ketone, which was purified byusing column chromatography to afford the ketone 3.0 g (87%) as a paleyellow oil.

[0642] Step B

[0643] To a solution of ketone (1.0 g) from Step A above in THF (5.0 mL)at 0° C. was added R-methyl oxazoborolidine (1.2 mL, 1 M in toluene)dropwise followed by addition of a solution of borane complexed withdimethyl sulfide (1.85 mL, 2M in THF). The reaction mixture was stirredfor 30 minutes at 0° C. and than at room temperature for one hour. Thereaction mixture was cooled to 0° C. and MeOH was added carefully. Themixture was stirred for 20 minutes and was concentrated under reducedpressure. The residue was extracted with ether, washed with water, 1 MHCl (10 mL), saturated sodium bicarbonate (10.0 mL) water and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andremoval of solvent afforded the crude alcohol which was purified bysilica gel chromatography to afford the pure alcohol 0.91 g (91%) asyellow oil.

PREPARATIVE EXAMPLE 602

[0644]

[0645] Step A

[0646] An equimolar mixture of 2-methylfuran (1.0 g) and anhydride (2.6g) was mixed with SnCl₄ (0.05 mL) and heated at 100° C. for 3 hours.After cooling the reaction mixture, water (10 mL) was added, followed bysaturated sodium carbonate solution until it becomes alkaline. Thereaction mixture was extracted with ether several times and the combinedether layer was washed with water, brine and dried over anhydrous sodiumsulfate. Filtration and removal of solvent afforded the crude ketone,which was purified by using silica gel chromatography to afford theketone 0.9 g (43%) as a yellow oil.

[0647] Step B

[0648] The title alcohol was obtained following a similar procedure setforth in Preparative Example 601.

PREPARATIVE EXAMPLE 603

[0649]

[0650] To a solution of 5-methyl furan-2-aldehyde (1.0 g) and3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added indiumpowder (1.66 g) and lithium iodide (50.0 mg). The reaction mixture wasstirred over night, diluted with water and extracted with ether. Theether layer was washed with water, brine and purified by silica gelchromatography to afford the pure alcohol 2.8 g (92%).

PREPARATIVE EXAMPLES 604-611

[0651] Following a similar procedure set forth in WO 02/083624Preparative Examples 13.25 or 601 the following Alcohols were prepared.Prep Ex Furan Electrophile Alcohol Yield 604

86% 605

69% 606

84% 607

82% 608

60% 609

65% 610

82% 611

89%

PREPARATIVE EXAMPLES 620-631

[0652] Following a similar procedure to that set forth in WO 02/083624Preparative Example 13.25 the following Amines were prepared from thecorresponding Alcohols. Prep % Ex ALCOHOL AMINE YIELD 620

28 621

58 622

69 623

81 624

82 625

45 626

57 627

58 628

54 629

53 630

50 631

82%

PREPARATIVE EXAMPLE 640-641

[0653] Following the procedures set forth in WO 02/083624 PreparativeExample 19 but using the amine from the Preparative Example indicated inthe Table below, the cyclobutenedione intermediates were obtained. Aminefrom 1. Yield Prep Ex. Prep Ex. Product 2. MH⁺ 640 600 Step B

1. 60% 2. 138 641 600 Step D

1. 65% 2. 138

EXAMPLES 360.109-360.117

[0654] Following the procedure set forth in WO 02/083524 Example 261 butusing the 5 amine from the Preparative Example indicated in the tablebelow, the following cyclobutenedione products were obtained. 1. Yield2. MH⁺ Ex. Amine Product 3. mp (° C.) 360.109 75.10A

1. 67% 2. 410.1 3. 119-121 360.110 75.10B

1. 71% 2. 412 3. 102 360.111 75.10C

1. 64% 2. 440.1 3. 91-93 360.112 75.10D

1. 79% 3. 412 3. 111-113 360.113 75.10E

1. 20% 2. 440.1 3. 130 (DEC) 360.114 75.10F

1. 61% 2. 438.1 3. 117-119 360.115 75.10G

1. 61% 2. 440.1 3. 117-119 360.116 75.10H

1. 81% 2. 452 3. 118 360.117 75.10J

1. 65% 2. 466 3. 109

EXAMPLES 368.32-368.45

[0655] Following the procedure set forth in WO 02/083624 Example 261 butusing the amine in the table below and the cyclobutenedione intermediatefrom the Preparative Example indicated, the following cyclobutenedioneproducts were obtained. 1. Yield Prep. 2. MH⁺ Ex. Amine Ex. Product 3.mp (° C.) 368.32 75.49

23.14

1. 58% 2. 471.1 3. 149 368.33 75.1

23.15A

1. 33% 2. 440.1 3. 181 368.34 75.9

23.15A

1. 56% 2. 468 3. 180 368.35 75.N6

23.15A

1. 28% 2. 480 3. 186 368.36 75.N8

23.15A

1. 48% 2. 494 3. 112.5 368.37 75.1

23.15B

1. 58% 2. 592 3. 177-179 368.38 75.49

23.15C

1. 69% 2. 516 3. 88-90 368.39 75.49

23.15D

1. 80% 2. 530 3. 134-137 368.40 75.49

23.15E

1. 57% 2. 454 3. 138-140 368.41 75.49

19.2

1. 26% 2. 507 3. 162-164 368.42  3 23.25

1. 82% 2. 466 3. 141-143 368.43  3 23.26

1. 67% 2. 480 3. 139 dec 368.44 13.29 23.16

1. 29% 2. 480 3. 112-114 368.45 13.29 23.26

1. 88% 2. 508 3. 190 dec

EXAMPLES 1200-1212

[0656] Following the procedure set forth in WO 02/083624 Example 261 butusing the prepared amine indicated in the table below, the followingcyclobutenedione products were obtained. 1. Yield 2. MH⁺ Ex. AmineProduct 3. mp (° C.) 1200

1. 61.3% 2. 451.4 3. 108.6 1201

1. 54% 2. 439.5 3. 117.8 1202

1. 80% 2. 439.5 3. 128-131.8 1203

1. 75% 2. 423.4 3. 118-119 1204

1. 74% 2. 447.4 3. 108-111 1205

1. 42% 2. 415.42 3. 136-140 1206

1. 46% 2. 423.4 3. 114-117 1207

1. 35% 2. 433.1 3. 123-128 1208

1. 42% 2. 423.4 3. 118-121 1209

1. 51% 2. 415.4 3. 112-117 1210

1. 44% 2. 415.4 3. 115-120 1211

1. 48% 2. 445.4 3. 105-110

EXAMPLES 1300-1309

[0657] Following the procedure set forth in WO 02/083624 Example 261 butusing the prepared amine in the table below and the cyclobutenedioneintermediate from the Preparative Example indicated (from either thisApplication of from WO 02/083624), the following cyclobutenedioneproducts were obtained. 1. Yield Prep. 2. MH⁺ Ex. Amine Ex. Product 3.mp (20° C.) 1300

640

1. 35% 2. 390.4 3. 100 1301

641

1. 78% 2. 390.4 3. 130 1302

23.9

1. 48% 2. 483.4 3. 116 1303

23.9

1. 46% 2. 443.5 3. 106 1304

23.9

1. 40% 2. 445.54 3. 102 1305

23.9

1. 51% 2. 413.4 3. 98 1306

23.9

1. 78% 2. 405.5 3. 246 1307

23.9

1. 83% 2. 439.5 3. 129 1308

23.15A

1. 11% 2. 519.47 3. 123 1309

23.15A

1. 47% 2. 475 3. 113 1310

23.15F

1. 55% 2. 496.1 3. 123-125 1311

23.15F

1. 74% 2. 468.1 3. 116-118

EXAMPLES 1500-1503

[0658] If one were to follow the procedure set forth in WO 02/083624Example 261 but using the prepared amine and the cyclobutenedioneintermediate in the table below from the Preparative Example indicated,the following cyclobutenedione products could be obtained.Cyclobutenedione Amine from intermediate Ex. Prep Ex. from Prep ExProduct 1500

26

1501

23.15F

1502

24

1503

24

1504

25

1505

25

[0659] While the present invention has been described in conjunctionwith specific embodiments set forth above, many alternatives,modifications and variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention.

What is claimed is:
 1. A method of treating a CXC chemokine mediateddisease comprising administering to a patient in need of such treatment,a therapeutically effective amount of: (a) One or more compounds of theformula (I):

or a pharmaceutically acceptable salt or solvate thereof; and (b) One ormore drugs, agents or therapeutics useful for the treatment of chemokinemediated diseases; wherein for said compounds of formula (I): A isselected from the group consisting of:

wherein the above rings of said A groups are substituted with 1 to 6substituents each independently selected from the group consisting of:R⁹ groups;

wherein one or both of the above rings of said A groups are substitutedwith 1 to 6 substituents each independently selected from the groupconsisting of: R⁹ groups;

wherein the above phenyl rings of said A groups are substituted with 1to 3 substituents each independently selected from the group consistingof: R⁹ groups; and

B is selected from the group consisting of

n is 0 to 6; p is 1 to 5; X is O, NH, or S; Z is 1 to 3; R² is selectedfrom the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO₂NR¹³R¹⁴,—NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³, —NR¹³R¹⁴, —C(O)NR¹³R¹⁴,—C(O)NHOR¹³, —C(O)NR¹³OH, —S(O₂)OH, —OC(O)R¹³, an unsubstitutedheterocyclic acidic functional group, and a substituted heterocyclicacidic functional group; wherein there are 1 to 6 substituents on saidsubstituted heterocyclic acidic functional group each substituent beingindependently selected from the group consisting of: R⁹ groups; each R³and R⁴ is independently selected from the group consisting of: hydrogen,cyano, halogen, alkyl, alkoxy, —OH, —CF₃, —OCF₃, —NO₂, —C(O)R¹³,—C(O)oR¹³, —C(O)NHR¹⁷, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴, —SO_((t))R¹³,—C(O)NR¹³OR¹⁴, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl,

wherein there are 1 to 6 substituents on said substituted aryl group andeach substituent is independently selected from the group consisting of:R⁹ groups; and wherein there are 1 to 6 substituents on said substitutedheteroaryl group and each substituent is independently selected from thegroup consisting of: R⁹ groups; each R⁵ and R⁶ are the same or differentand are independently selected from the group consisting of hydrogen,halogen, alkyl, alkoxy, —CF₃, —OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³,—C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, cyano, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl group;wherein there are 1 to 6 substituents on said substituted aryl group andeach substituent is independently selected from the group consisting of:R⁹ groups; and wherein there are 1 to 6 substituents on said substitutedheteroaryl group and each substituent is independently selected from thegroup consisting of: R⁹ groups; each R⁷ and R⁸ is independently selectedfrom the group consisting of: H, unsubstituted or substituted alkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or moresubstituents on said substituted R⁷ and R⁸ groups, wherein eachsubstitutent is independently selected from the group consisting of: a)halogen, b) —CF₃, c) —COR¹³, d) —OR¹³, e) —NR¹³R¹⁴ f) —NO₂, g) —CN, h)—SO₂OR¹³, i) —Si(alkyl)₃, wherein each alkyl is independently selected,j) —Si(aryl)₃, wherein each alkyl is independently selected, k)—(R¹³)₂R¹⁴Si, wherein each R¹³ is independently selected, l) —CO₂R¹³, m)—C(O)NR¹³R¹⁴, n) —SO₂NR¹³R¹⁴, o) —SO₂R¹³, p) —OC(O)R¹³, q)—OC(O)NR¹³R¹⁴, r) —NR¹³C(O)R¹⁴, and s) —NR¹³CO₂R¹⁴; R^(8a) is selectedfrom the group consisting of: hydrogen, alkyl, cycloalkyl andcycloalkylalkyl; each R⁹ is independently selected from the groupconsisting of: a) —R¹³, b) halogen, c) —CF₃, d) —COR¹³, e) —OR¹³, f)—NR¹³R¹⁴, g) —NO₂, h) —CN, i) —SO₂R¹³, j) —SO₂NR¹³R¹⁴, k) —NR¹³COR¹⁴, l)—CONR¹³R¹⁴, m) —NR¹³CO₂R¹⁴, n) —CO₂R¹³, o)

p) alkyl substituted with one or more —OH groups, q) alkyl substitutedwith one or more —NR¹³R¹⁴ group, and r) —N(R¹³)SO₂R¹⁴; each R¹⁰ and R¹¹is independently selected from the group consisting of R¹³, halogen,—CF₃, —OCF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —OH, —C(O)OR¹³, —SH,—SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—C(O)NR¹³R¹⁴, —C(O)NR¹³0R¹⁴, —OC(O)R¹³ and cyano; R¹² is selected fromthe group consisting of: hydrogen, —C(O)OR¹³, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted alkyl, unsubstituted or substitutedcycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group;wherein there are 1 to 6 substituents on the substituted R¹² groups andeach substituent is independently selected from the group consisting of:R⁹ groups; each R¹³ and R¹⁴ is independently selected from the groupconsisting of: H, unsubstituted or substituted alkyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, unsubstituted or substituted heterocyclic,unsubstituted or substituted fluoroalkyl, and unsubstituted orsubstituted heterocycloalkylalkyl (wherein “heterocyloalkyl” meansheterocyclic); wherein there are 1 to 6 substituents on said substitutedR¹³ and R¹⁴ groups and each substituent is independently selected fromthe group consisting of: alkyl, —CF₃, —OH, alkoxy, aryl, arylalkyl,fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,—N(R⁴⁰)₂, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —S(O)_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵provided that R¹⁵ is not H, halogen, and —NHC(O)NR¹⁵R¹⁶; or R¹³ and R¹⁴taken together with the nitrogen they are attached to in the groups—C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted or substitutedsaturated heterocyclic ring (preferably a 3 to 7 membered heterocyclicring), said ring optionally containing one additional heteroatomselected from the group consisting of: O, S and NR¹⁸; wherein there are1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., there is 1 to 3 substituents on the ring formed when the R¹³ andR¹⁴ groups are taken together with the nitrogen to which they are bound)and each substituent is independently selected from the group consistingof: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶, —NHC(O)OR¹⁵, halogen, and aheterocycloalkenyl group; each R¹⁵ and R¹⁶ is independently selectedfrom the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl andheteroaryl; R¹⁷ is selected from the group consisting of: —SO₂alkyl,—SO₂aryl, —SO₂cycloalkyl, and —SO₂heteroaryl; R¹⁸ is selected from thegroup consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and—C(O)NR¹⁹R²⁰; each R¹⁹ and R²⁰ is independently selected from the groupconsisting of: alkyl, aryl and heteroaryl; R³⁰ is selected from thegroup consisting of: alkyl, cycloalkyl, —CN, —NO₂, or —SO₂R¹⁵ providedthat R¹⁵ is not H; each R³¹ is independently selected from the groupconsisting of: unsubstituted alkyl, unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl and unsubstituted or substitutedcycloalkyl; wherein there are 1 to 6 substituents on said substitutedR³¹ groups and each substituent is independently selected from the groupconsisting of: alkyl, halogen and —CF₃; each R⁴⁰ is independentlyselected from the group consisting of: H, alkyl and cycloalkyl; g is 1or 2; and t is 0, 1 or
 2. 2. The method of claim 1 wherein B is selectedfrom the group consisting of:

and R³ for this B group is selected from the group consisting of:—C(O)NR¹³R¹⁴,

and all other substituents are as defined in claim
 1. 3. The method ofclaim 3 wherein substituent A is

wherein the furan ring is unsubstituted or substitued.
 4. The method ofclaim 1 wherein B is:

R² is —OH, R¹³ and R¹⁴ are independently selected from the groupconsisting of H and alkyl.
 5. The method of claim 3 wherein wherein Bis:

R² is —OH, R¹³ and R¹⁴ are independently selected from the groupconsisting of H and alkyl.
 6. The method of claim 1 wherein B isselected from the group consisting of:


7. The method of claim 6 wherein B is


8. The method of claim 1 wherein A is selected from the group consistingof:


9. The method of claim 8 wherein A is selected from the group consistingof:


10. The method of claim 9 wherein A is


11. The method of claim 1 wherein said compounds of formula (I) areselected from the group consisting of:


12. The method of claim 1 wherein said compounds of formula (I) areselected from the group consisting of:


13. The method of claim 1 wherein said compounds of formula (I) areselected from the group consisting of:


14. The method of claim 13 wherein said compound is a calcium or sodiumsalt.
 15. The method of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 16. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 17. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 18. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 19. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 20. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 21. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 22. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 23. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 24. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 25. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 26. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 27. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 28. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 29. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 30. The methodof claim 25 wherein said compound is a calcium or sodium salt.
 31. Themethod of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 32. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 33. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 34. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 35. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 36. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 37. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 38. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 39. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 40. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 41. The methodof claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 42. The methodof claim 1 wherein said drug, agent or therapeutic used in combinationwith said compounds of formula (I) is selected from the group consistingof (a) a disease modifying antirheumatic drug; (b) a nonsteroidalanitinflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biologicalresponse modifier and (h) other anti-inflammatory agents or therapeuticsuseful for the treatment of chemokine mediated diseases.
 43. The methodof claim 42 wherein said disease modifying antirheumatic drug isselected from the group consisting of methotrexate, azathioptrineluflunomide, penicillamine, gold salts, mycophenolate, mofetil andcyclophosphamide.
 44. The method of claim 42 wherein said nonsteroidalanitinflammatory drug is selected from the group consisting ofpiroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen.
 45. Themethod of claim 42 wherein said COX-2 selective inhibitor is selectedfrom the group consisting of rofecoxib and celecoxib.
 46. The method ofclaim 42 wherein said COX-1 inhibitor is piroxicam.
 47. The method ofclaim 42 wherein said immunosuppressive is selected from the groupconsisting of methotrexate, cyclosporin, leflunimide, tacrolimus,rapamycin and sulfasalazine.
 48. The method of claim 42 wherein saidsteroid is selected from the group consisting of β-methasone,prednisone, cortisone, prednisolone and dexamethasone.
 49. The method ofclaim 42 wherein said biological response modifier is selected from thegroup consisting of anti-TNF antagonists, IL-1 antagonists, anti-CD40,anti-CD28, IL-10 and anti-adhesion molecules.
 50. The method of claim 42wherein said other anti-inflammatory agents or therapeutics are selectedfrom the group consisting of p38 kinase inhibitors, PDE4 inhibitors,TACE inhibitors, chemokine receptor antagonists, thalidomide,leukotriene inhibitors and other small molecule inhibitors ofpro-inflammatory cytokine production.
 51. The method of claim 1 whereinsaid chemokine mediated disease is selected from the group consisting ofpsoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease,arthritis, inflammatory bowel disease, Crohn's disease, ulcerativecolitis, septic shock, endotoxic shock, gram negative sepsis, toxicshock syndrome, stroke, cardiac and renal reperfusion injury,glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. hostreaction, allograft rejections, malaria, acute respiratory distresssyndrome, delayed type hypersensitivity reaction, atherosclerosis,cerebral and cardiac ischemia, osteoarthritis, multiple sclerosis,restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses,herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associatedvirus, meningitis, cystic fibrosis, pre-term labor, cough, pruritis,multi-organ dysfunction, trauma, strains, sprains, contusions, psoriaticarthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury,CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitialpneumonitis, hypersensitivity, crystal induced arthritis, acute andchronic pancreatitis, acute alcoholic hepatitis, necrotizingenterocolitis, chronic sinusitis, angiogenic ocular disease, ocularinflammation, retinopathy of prematurity, diabetic retinopathy, maculardegeneration with the wet type preferred and corneal neovascularization,polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiacdisease, esophagitis, glossitis, airflow obstruction, airwayhyperresponsiveness, bronchiectasis, bronchiolitis, bronchiolitisobliterans, chronic bronchitis, cor pulmonae, cough, dyspnea, emphysema,hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations,hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonaryhypertension, right ventricular hypertrophy, peritonitis associated withcontinuous ambulatory peritoneal dialysis (CAPD), granulocyticehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusionmismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burntherapy, periodontitis and early transplantation.
 52. The method ofclaim 1 wherein said chemokine mediated disease is a pulmonary diseaseand said one or more drugs, agents or therapeutics are selected from thegroup consisting of: glucocorticoids, 5-lipoxygenase inhibitors, β-2adrenoceptor agonists, muscarinic M1 and M3 antagonists, muscarinic M2agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotrieneantagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastaseinhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase Dinhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamineagonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-bagonists, nociceptin agonists, expectorants, mucolytic agents,decongestants, antioxidants, anti-IL-8 anti-bodies, anti-IL-5antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesionmolecule inhibitors, and growth hormones.
 53. The method of claim 52wherein said pulmonary disease is COPD, asthma or cystic fibrosis. 54.The method of claim 1 wherein said chemokine mediated disease ismultiple sclerosis and said one or more drugs, agents or therapeuticsare selected from the group consisting of methotrexate, cyclosporin,leflunimide, sulfasalazine, β-methasone, interferon, glatiramer acetate,prednisone, etonercept, and infliximab.
 55. The method of claim 1wherein said chemokine mediated disease is rheumatoid arthritis and saidone or more drugs, agents or therapeutics are selected from the groupconsisting of a COX-2 inhibitor, a COX inhibitor, an immunosuppressive,a steroid, a PDE IV inhibitor, an anti-TNF-α compound, MMP inhibitors,glucocorticoids, chemokine inhibitors, CB2-selective inhibiitors, andother classes of compounds indicated for the treatment of rheumatoidarthritis.
 56. The method of claim 1 wherein said chemokine mediateddisease is stroke and cardiac reperfusion injury and said one or moredrugs, agents or therapeutics are selected from the group consisting ofthrombolitics, antiplatelet agents, gpIIb/IIIa antagonist,anticoagulants, other compounds indicated for the treatment ofrheumatoid arthritis and formulations thereof.
 57. The method of claim 1wherein said chemokine mediated disease is stroke and cardiacreperfusion injury and said one or more drugs, agents or therapeuticsare selected from the group consisting of tenecteplase, TPA, alteplase,abciximab, eftiifbatide, heparin and formulations thereof.
 58. Acompound of selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.
 59. Thecompound of claim 58 wherein said compound is a sodium salt.
 60. Thecompound of claim 58 wherein said compound is a calcium salt.
 61. Thecompound of claim 58 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 62. Thecompound of claim 58 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 63. Thecompound of claim 58 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 64. Thecompound of claim 58 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 65. Thecompound of claim 58 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.